Usp 797GC

Revision Bulletin 797 Pharmaceutical CompoundingSterile Preparations 1
Change to read: quality standards for CSPs of drugs and nutrients

based on current scientific information and best
sterile compounding practices. The use of technol-
ogies, techniques, materials, and procedures other
than those described in this chapter is not prohib-
797 PHARMACEUTICAL ited so long as they have been proven to be equiva-
lent or superior with statistical significance to
COMPOUNDING
those described herein. The standards in this chap-
STERILE PREPARATIONS
ter do not pertain to the clinical administration of
CSPs to patients via application, implantation, in-
fusion, inhalation, injection, insertion, instillation,
and irrigation, which are the routes of administra-
INTRODUCTION
tion. Four specific categories of CSPs are de-
The objective of this chapter is to describe con- scribed in this chapter: low-risk level, medium-risk
ditions and practices to prevent harm, including level, and high-risk level, and immediate use. Ster-
death, to patients that could result from (1) micro- ile compounding differs from nonsterile com-
bial contamination (nonsterility), (2) excessive pounding (see Pharmaceutical Compound-
bacterial endotoxins, (3) variability in the intended ingNonsterile Preparations 795 and Good
strength of correct ingredients that exceeds either Compounding Practices 1075) primarily by re-
monograph limits for official articles (see offi- quiring the maintenance of sterility when com-
cial and article in the General Notices and Re- pounding exclusively with sterile ingredients and
quirements) or 10% for nonofficial articles, (4) un- components ( i.e., with immediate-use CSPs, low-
intended chemical and physical contaminants, and risk level CSPs, and medium-risk level CSPs) and
(5) ingredients of inappropriate quality in com- the achievement of sterility when compounding
pounded sterile preparations (CSPs). Contami- with nonsterile ingredients and components (i.e.,
nated CSPs are potentially most hazardous to pa- with high-risk level CSPs). Some differences be-
tients when administered into body cavities, tween standards for sterile compounding in this
central nervous and vascular systems, eyes, and chapter and those for nonsterile compounding in
joints, and when used as baths for live organs and Pharmaceutical CompoundingNonsterile Prepa-
tissues. When CSPs contain excessive bacterial en- rations 795 include, but are not limited to, ISO-
dotoxins (see Bacterial Endotoxins Test 85), they classified air environments (see Table 1); person-
are potentially most hazardous to patients when nel garbing and gloving; personnel training and
administered into the central nervous system. testing in principles and practices of aseptic ma-
Despite the extensive attention in this chapter to nipulations and sterilization; environmental quality
the provision, maintenance, and evaluation of air specifications and monitoring; and disinfection of
quality, the avoidance of direct or physical contact gloves and surfaces of ISO Class 5 (see Table 1)
contamination is paramount. It is generally ac- sources.
knowledged that direct or physical contact of criti-
cal sites of CSPs with contaminants, especially mi-
crobial sources, poses the greatest probability of
risk to patients. Therefore, compounding personnel
must be meticulously conscientious in precluding
contact contamination of CSPs both within and
outside ISO Class 5 (see Table 1) areas.
To achieve the above five conditions and prac-
tices, this chapter provides minimum practice and
Copyright 2008 The United States Pharmacopeial Convention All Rights Reserved.
2 797 Pharmaceutical CompoundingSterile Preparations Revision Bulletin
Table 1. ISO Classification of Particulate Mat- thalmic drops and ointments, and tissue
ter in Room Air (limits are in particles of 0.5 implants.
m and larger per cubic meter [current ISO] and
(2) Manufactured sterile products that are either
cubic feet [former Federal Standard No. 209E,
prepared strictly according to the instructions
FS 209E])
*
appearing in manufacturers approved label-
ing (product package inserts) or prepared dif- Class Name Particle Count
ferently than published in such labeling.
FS
[NOTEThe FDA states that Compounding
ISO U.S. FS 209E,
does not include mixing, reconstituting, or
Class 209E ISO, m
3
ft
3
similar acts that are performed in accordance
3 Class 1 35.2 1
with the directions contained in approved la-
4 Class 10 352 10
beling provided by the products manufac-
5 Class 100 3,520 100
turer and other manufacturer directions con-
6 Class 1,000 35,200 1,000
sistent with that labeling [(21 USC 321 (k)
7 Class10,000 352,000 10,000
and (m)]. However, the FDA-approved label-
8 Class100,000 3,520,000 100,000
ing (product package insert) rarely describes
*
Adapted from former Federal Standard No. 209E, General Servic- environmental quality (e.g., ISO Class air des-
es Administration, Washington, DC, 20407 (September 11, 1992)
ignation, exposure durations to non-ISO
and ISO 14644-1: 1999, Cleanrooms and associated controlled en-
vironmentsPart 1: Classification of air cleanliness. For example,
classified air, personnel garbing and gloving,
3,520 particles of 0.5 m per m
3
or larger (ISO Class 5) is equiva-
and other aseptic precautions by which sterile
lent to 100 particles per ft
3
(Class 100) (1 m
3
=35.2 ft
3
).
products are to be prepared for administra-
The standards in this chapter are intended to ap-
tion). Beyond-use exposure and storage dates
ply to all persons who prepare CSPs and all places
or times (see General Notices and Require-
where CSPs are prepared (e.g., hospitals and other
ments and Pharmaceutical Compound-
healthcare institutions, patient treatment clinics,
ingNonsterile Preparations 795) for ster-
pharmacies, physicians practice facilities, and
ile products that have been either opened or
other locations and facilities in which CSPs are
prepared for administration are not specified
prepared, stored, and transported). Persons who
in all package inserts for all sterile products.
perform sterile compounding include pharmacists,
Furthermore, when such durations are speci-
nurses, pharmacy technicians, and physicians.
fied, they may refer to chemical stability and
These terms recognize that most sterile compound-
not necessarily to microbiological purity or
ing is performed by or under the supervision of
safety.]
pharmacists in pharmacies and also that this chap-
ter applies to all healthcare personnel who prepare,
ORGANIZATION OF THIS CHAPTER
store, and transport CSPs. For the purposes of this
chapter, CSPs include any of the following:
The sections in this chapter are organized to fa-
(1) Compounded biologics, diagnostics, drugs,
cilitate the practitioners understanding of the fun-
nutrients, and radiopharmaceuticals, including
damental accuracy and quality practices for pre-
but not limited to the following dosage forms
paring CSPs. They provide a foundation for the
that must be sterile when they are adminis-
development and implementation of essential pro-
tered to patients: aqueous bronchial and nasal
cedures for the safe preparation of low-risk, med-
inhalations, baths and soaks for live organs
ium-risk, and high-risk level CSPs and immediate-
and tissues, injections (e.g., colloidal disper-
use CSPs, which are classified according to the po-
sions, emulsions, solutions, suspensions), irri-
tential for microbial, chemical, and physical con-
gations for wounds and body cavities, oph-
tamination. The chapter is divided into the follow-
ing main sections:
Definitions entry, CSP labeling, and other high-particulate-
generating activities are performed. It is also a Responsibility of Compounding Personnel
transition area that (1) provides assurance that CSP Microbial Contamination Risk Levels
pressure relationships are constantly maintained so Personnel Training and Evaluation in Aseptic
that air flows from clean to dirty areas and (2) re- Manipulation Skills
duces the need for the heating, ventilating, and air- Immediate-Use CSPs
conditioning (HVAC) control system to respond to Single-Dose and Multiple-Dose Containers
large disturbances.
1
Hazardous Drugs as CSPs
Radiopharmaceuticals as CSPs
Aseptic Processing (see Microbiological Evalu-
Allergen Extracts as CSPs
ation of Clean Rooms and Other Controlled Envi-
Verification of Compounding Accuracy and
ronments 1116)A mode of processing pharma-
Sterility
ceutical and medical products that involves the
Environmental Quality and Control
separate sterilization of the product and of the
Suggested Standard Operating Procedures
package (containersclosures or packaging ma-
(SOPs)
terial for medical devices) and the transfer of the
Elements of Quality Control
product into the container and its closure under at
Verification of Automated Compounding De-
least ISO Class 5 (see Table 1) conditions.
vices (ACDs) for Parenteral Nutrition
Beyond-Use Date (BUD) (see General Notices
Compounding
and Requirements and Pharmaceutical Com-
Finished Preparation Release Checks and
poundingNonsterile Preparations 795)For
Tests
the purpose of this chapter, the date or time after
Storage and Beyond-Use Dating
which a CSP shall not be stored or transported.
Maintaining Sterility, Purity, and Stability of
The date is determined from the date or time the
Dispensed and Distributed CSPs
preparation is compounded.
Patient or Caregiver Training
Biological Safety Cabinet (BSC)A ventilated
Patient Monitoring and Adverse Events
cabinet for CSPs, personnel, product, and environ-
Reporting
mental protection having an open front with in-
Quality Assurance (QA) Program
ward airflow for personnel protection, downward
Abbreviations and Acronyms
high-efficiency particulate air (HEPA)-filtered
Appendices IV
laminar airflow for product protection, and HEPA-
The requirements and recommendations in this
filtered exhausted air for environmental protection.
chapter are summarized in Appendix I. A list of ab-
Buffer AreaAn area where the primary engi-
breviations and acronyms is included at the end of
neering control (PEC) is physically located. Activ-
the main text, before the Appendices.
ities that occur in this area include the preparation
All personnel who prepare CSPs shall be re-
and staging of components and supplies used when
sponsible for understanding these fundamental
compounding CSPs.
practices and precautions, for developing and im-
plementing appropriate procedures, and for contin-
Clean Room (see Microbiological Evaluation of
ually evaluating these procedures and the quality
Clean Rooms and Other Controlled Environments
of final CSPs to prevent harm.
1116 and also the definition of Buffer Area)A
room in which the concentration of airborne parti-
cles is controlled to meet a specified airborne par- DEFINITIONS
ticulate cleanliness class. Microorganisms in the
Ante-AreaAn ISO Class 8 (see Table 1) or
environment are monitored so that a microbial
better area where personnel hand hygiene and 1
See American Society of Heating, Refrigerating and Air-Condi-
garbing procedures, staging of components, order tioning Engineers, Inc. (ASHRAE), Laboratory Design Guide.
level for air, surface, and personnel gear are not exposed to unidirectional HEPA-filtered air, also
exceeded for a specified cleanliness class. known as first air.
Compounding Aseptic Containment Isolator
DisinfectantAn agent that frees from infec-
(CACI)A compounding aseptic isolator (CAI)
tion, usually a chemical agent but sometimes a
designed to provide worker protection from expo-
physical one, and that destroys disease-causing
sure to undesirable levels of airborne drug
pathogens or other harmful microorganisms but
throughout the compounding and material transfer
may not kill bacterial and fungal spores. It refers to
processes and to provide an aseptic environment
substances applied to inanimate objects.
for compounding sterile preparations. Air ex-
First AirThe air exiting the HEPA filter in a
change with the surrounding environment should
unidirectional air stream that is essentially particle
not occur unless the air is first passed through a
free.
microbial retentive filter (HEPA minimum) system
Hazardous DrugsDrugs are classified as haz-
capable of containing airborne concentrations of
ardous if studies in animals or humans indicate
the physical size and state of the drug being com-
that exposures to them have a potential for causing
pounded. Where volatile hazardous drugs are pre-
cancer, developmental or reproductive toxicity, or
pared, the exhaust air from the isolator should be
harm to organs. (See current NIOSH publication.)
appropriately removed by properly designed build-
Labeling [see General Notices and Require-
ing ventilation.
ments and 21 USC 321 (k) and (m)]A term that
Compounding Aseptic Isolator (CAI)A
designates all labels and other written, printed, or
form of isolator specifically designed for com-
graphic matter on an immediate container of an ar-
pounding pharmaceutical ingredients or prepara-
ticle or preparation or on, or in, any package or
tions. It is designed to maintain an aseptic com-
wrapper in which it is enclosed, except any outer
pounding environment within the isolator
shipping container. The term label designates
throughout the compounding and material transfer
that part of the labeling on the immediate
processes. Air exchange into the isolator from the
container.
surrounding environment should not occur unless
Media-Fill Test (see Microbiological Evalua-
the air has first passed through a microbially reten-
tion of Clean Rooms and Other Controlled Envi-
tive filter (HEPA minimum).
2
ronments 1116)A test used to qualify aseptic
Critical AreaAn ISO Class 5 (see Table 1)
technique of compounding personnel or processes
environment.
and to ensure that the processes used are able to
Critical SiteA location that includes any com-
produce sterile product without microbial contami-
ponent or fluid pathway surfaces (e.g., vial septa,
nation. During this test, a microbiological growth
injection ports, beakers) or openings (e.g., opened
medium such as SoybeanCasein Digest Medium
ampuls, needle hubs) exposed and at risk of direct
is substituted for the actual drug product to simu-
contact with air (e.g., ambient room or HEPA fil-
late admixture compounding.
3
The issues to con-
tered), moisture (e.g., oral and mucosal secre-
sider in the development of a media-fill test are
tions), or touch contamination. Risk of microbial
media-fill procedures, media selection, fill volume,
particulate contamination of the critical site in-
incubation, time and temperature, inspection of
creases with the size of the openings and exposure
filled units, documentation, interpretation of re-
time.
sults, and possible corrective actions required.
Direct Compounding Area (DCA)A critical
Multiple-Dose Container (see General Notices
area within the ISO Class 5 (see Table 1) primary
and Requirements and Containers for Injections
engineering control (PEC) where critical sites are
under Injections 1)A multiple-unit container
2
CETA Applications Guide for the Use of Compounding Isolators in
Compounding Sterile Preparations in Healthcare Facilities, CAG-
3
U.S. Food and Drug Administration, Guidance for Industry, Sterile
001-2005, Controlled Environment Testing Association (CETA), Drug Products Produced by Aseptic ProcessingCurrent Good
November 8, 2005. Manufacturing Practice, September 2004.
for articles or preparations intended for parenteral suant to the order of a licensed prescriber; the arti-
administration only and usually containing antimi- cle may or may not contain sterile products.
crobial preservatives. The beyond-use date (BUD)
ProductA commercially manufactured sterile
for an opened or entered (e.g., needle-punctured)
drug or nutrient that has been evaluated for safety
multiple-dose container with antimicrobial pre-
and efficacy by the FDA. Products are accompa-
servatives is 28 days (see Antimicrobial Effective-
nied by full prescribing information, which is com-
ness Testing 51), unless otherwise specified by
monly known as the FDA-approved manufactur-
the manufacturer.
ers labeling or product package insert.
Negative Pressure RoomA room that is at a
Positive Pressure RoomA room that is at a
lower pressure than the adjacent spaces and, there-
higher pressure than the adjacent spaces and,
fore, the net flow of air is into the room.
1
therefore, the net airflow is out of the room.
1
Pharmacy Bulk Package (see Containers for
Single-Dose Container (see General Notices
Injections under Injections 1)A container of a
and Requirements and Containers for Injections
sterile preparation for parenteral use that contains
under Injections 1)A single-dose container is a
many single doses. The contents are intended for
single-unit container for articles (see General No-
use in a pharmacy admixture program and are re-
tices and Requirements) or preparations intended
stricted to the preparation of admixtures for infu-
for parenteral administration only. It is intended
sion or, through a sterile transfer device, for the
for a single use. A single-dose container is labeled
filling of empty sterile syringes. The closure shall
as such. Examples of single-dose containers in-
be penetrated only one time after constitution with
clude prefilled syringes, cartridges, fusion-sealed
a suitable sterile transfer device or dispensing set,
containers, and closure-sealed containers when so
which allows measured dispensing of the contents.
labeled.
The pharmacy bulk package is to be used only in a
Segregated Compounding AreaA designated
suitable work area such as a laminar flow hood (or
space, either a demarcated area or room, that is re-
an equivalent clean air compounding area).
stricted to preparing low-risk level CSPs with 12-
Where a container is offered as a pharmacy bulk
hour or less BUD. Such area shall contain a device
package, the label shall (a) state prominently
that provides unidirectional airflow of ISO Class 5
Pharmacy Bulk PackageNot for Direct Infu-
(see Table 1) air quality for preparation of CSPs
sion, (b) contain or refer to information on proper
and shall be void of activities and materials that
techniques to help ensure safe use of the product,
are extraneous to sterile compounding.
and (c) bear a statement limiting the time frame in
Sterilizing Grade MembranesMembranes
which the container may be used once it has been
that are documented to retain 100% of a culture of
entered, provided it is held under the labeled stor-
10
7
microorganisms of a strain of Brevundimonas
age conditions.
(Pseudomonas) diminuta per square centimeter of
Primary Engineering Control (PEC)A de-
membrane surface under a pressure of not less than
vice or room that provides an ISO Class 5 (see Ta-
30 psi (2.0 bar). Such filter membranes are nomi-
ble 1) environment for the exposure of critical sites
nally at 0.22-m or 0.2-m nominal pore size, de-
when compounding CSPs. Such devices include,
pending on the manufacturers practice.
but may not be limited to, laminar airflow work-
Sterilization by FiltrationPassage of a fluid
benches (LAFWs), biological safety cabinets
or solution through a sterilizing grade membrane
(BSCs), compounding aseptic isolators (CAIs),
to produce a sterile effluent.
and compounding aseptic containment isolators
(CACIs). Terminal SterilizationThe application of a
PreparationA preparation, or a CSP, that is a lethal process (e.g., steam under pressure or
sterile drug or nutrient compounded in a licensed autoclaving) to sealed containers for the purpose
pharmacy or other healthcare-related facility pur- of achieving a predetermined sterility assurance
level of usually less than 10
6
, or a probability of correctly perform and document the following
less than one in one million of a nonsterile unit.
3
activities in their sterile compounding duties:
a. perform antiseptic hand cleansing and Unidirectional Flow (see footnote 3)An air-
disinfection of nonsterile compounding flow moving in a single direction in a robust and
surfaces; uniform manner and at sufficient speed to
b. select and appropriately don protective reproducibily sweep particles away from the criti-
garb; cal processing or testing area.
c. maintain or achieve sterility of CSPs in
ISO Class 5 (see Table 1) PEC devices
RESPONSIBILITY OF COMPOUNDING
and protect personnel and compounding
PERSONNEL
environments from contamination by ra-
Compounding personnel are responsible for en-
dioactive, cytotoxic, and chemotoxic
suring that CSPs are accurately identified, meas-
drugs (see Hazardous Drugs as CSPs and
ured, diluted, and mixed and are correctly purified,
Radiopharmaceuticals as CSPs);
sterilized, packaged, sealed, labeled, stored, dis-
d. identify, weigh, and measure ingredients;
pensed, and distributed. These performance re-
and
sponsibilities include maintaining appropriate
e. manipulate sterile products aseptically,
cleanliness conditions and providing labeling and
sterilize high-risk level CSPs, and label
supplementary instructions for the proper clinical
and quality inspect CSPs.
administration of CSPs.
2. Ingredients have their correct identity, quality,
Compounding supervisors shall ensure, through
and purity.
either direct measurement or appropriate informa-
3. Opened or partially used packages of ingredi-
tion sources, that specific CSPs maintain their la-
ents for subsequent use in CSPs are properly
beled strength within monograph limits for USP
stored under restricted access conditions in
articles, or within 10% if not specified, until their
the compounding facility. Such packages can-
BUDs. All CSPs are prepared in a manner that
not be used when visual inspection detects un-
maintains sterility and minimizes the introduction
authorized breaks in the container, closure,
of particulate matter.
and seal; when the contents do not possess the
A written quality assurance procedure includes expected appearance, aroma, and texture;
the following in-process checks that are applied, as when the contents do not pass identification
appropriate, to specific CSPs: accuracy and preci- tests specified by the compounding facility;
sion of measuring and weighing; the requirement and when either the BUD or expiration date
for sterility; methods of sterilization and purifica- has been exceeded.
tion; safe limits and ranges for strength of ingredi- 4. Water-containing CSPs that are nonsterile
ents, bacterial endotoxins, and particulate matter; during any phase of the compounding proce-
pH; labeling accuracy and completeness; BUD as- dure are sterilized within 6 hours after com-
signment; and packaging and storage require- pleting the preparation in order to minimize
ments. The dispenser shall, when appropriate and the generation of bacterial endotoxins.
practicable, obtain and evaluate results of testing 5. Sterilization methods achieve sterility of
for identity, strength, purity, and sterility before a CSPs while maintaining the labeled strength
CSP is dispensed. Qualified licensed healthcare of active ingredients and the physical integrity
professionals who supervise compounding and dis- of packaging.
pensing of CSPs shall ensure that the following 6. Measuring, mixing, sterilizing, and purifying
objectives are achieved: devices are clean, appropriately accurate, and
1. Compounding personnel are adequately effective for their intended use.
skilled, educated, instructed, and trained to 7. Potential harm from added substances and
differences in rate and extent of bioavailabil- the skill and knowledge of personnel who prepare
ity of active ingredients for other than oral CSPs. The rigor of in-process quality-control
route of administration are carefully evaluated checks and of postcompounding quality inspection
before such CSPs are dispensed and and testing increases with the potential hazard of
administered. the route of administration. For example, nonste-
8. Packaging selected for CSPs is appropriate to rility, excessive bacterial endotoxin contamination,
preserve the sterility and strength until the large errors in strength of correct ingredients, and
BUD. incorrect ingredients in CSPs are potentially more
9. While being used, the compounding environ- dangerous to patients when the CSPs are adminis-
ment maintains the sterility or the presteriliza- tered into the vascular and central nervous systems
tion purity, whichever is appropriate, of the than when administered by most other routes.
CSP.
10. Labels on CSPs list the names and amounts or
CSP MICROBIAL CONTAMINATION RISK
concentrations of active ingredients, and the
LEVELS
labels or labeling of injections (see Preserva-
The three contamination categories for CSPs de-
tion, Packaging, Storage, and Labeling in the
scribed in this section are assigned primarily ac-
General Notices and Requirements) list the
cording to the potential for microbial contamina-
names and amounts or concentrations of all
tion during the compounding of low-risk level
ingredients (see Injections 1). Before being
CSPs and medium-risk level CSPs or the potential
dispensed or administered, the clarity of solu-
for not sterilizing high-risk level CSPs, any of
tions is visually confirmed; also, the identity
which would subject patients to risk of harm, in-
and amounts of ingredients, procedures to
cluding death. High-risk level CSPs must be steril-
prepare and sterilize CSPs, and specific re-
ized before being administered to patients. The ap-
lease criteria are reviewed to ensure their ac-
propriate risk levellow, medium, or highis
curacy and completeness.
assigned according to the corresponding probabil-
11. BUDs are assigned on the basis of direct test-
ity of contaminating a CSP with (1) microbial con-
ing or extrapolation from reliable literature
tamination (e.g., microbial organisms, spores, en-
sources and other documentation (see Stabil-
dotoxins) and (2) chemical and physical
ity Criteria and Beyond-Use Dating under
contamination (e.g., foreign chemicals, physical
Pharmaceutical CompoundingNonsterile
matter). Potential sources of contamination in-
Preparations 795).
clude, but are not limited to, solid and liquid mat-
12. Procedures for measuring, mixing, dilution,
ter from compounding personnel and objects; non-
purification, sterilization, packaging, and la-
sterile components employed and incorporated
beling conform to the correct sequence and
before terminal sterilization; inappropriate condi-
quality established for the specified CSP.
tions within the restricted compounding environ-
13. Deficiencies in compounding, labeling, pack-
ment; prolonged presterilization procedures with
aging, and quality testing and inspection can
aqueous preparations; and nonsterile dosage forms
be rapidly identified and corrected.
used to compound CSPs.
14. When time and personnel availability so per-
mit, compounding manipulations and proce- The characteristics described below for low-,
dures are separated from postcompounding medium-, and high-risk level CSPs are intended as
quality inspection and review before CSPs are a guide to the breadth and depth of care necessary
dispensed. in compounding, but they are neither exhaustive
This chapter emphasizes the need to maintain nor prescriptive. The licensed healthcare profes-
high standards for the quality and control of sionals who supervise compounding are responsi-
processes, components, and environments and for ble for determining the procedural and environ-
mental quality practices and attributes that are 4. For a low-risk level preparation, in the ab-
necessary for the risk level they assign to specific sence of passing a sterility test (see Sterility
CSPs. Tests 71), the storage periods cannot exceed
the following time periods: before administra- These risk levels apply to the quality of CSPs
tion, the CSPs are properly stored and are ex- immediately after the final aseptic mixing or fill-
posed for not more than 48 hours at controlled ing or immediately after the final sterilization, un-
room temperature (see General Notices and less precluded by the specific characteristics of the
Requirements), for not more than 14 days at a preparation. Upon subsequent storage and shipping
cold temperature (see General Notices and of freshly finished CSPs, an increase in the risks of
Requirements), and for 45 days in solid frozen chemical degradation of ingredients, contamina-
state between 25 and 10. tion from physical damage to packaging, and per-
meability of plastic and elastomeric packaging is
Examples of Low-Risk Compounding
expected. In such cases, compounding personnel
1. Single-volume transfers of sterile dosage
are responsible for considering the potential addi-
forms from ampuls, bottles, bags, and vials
tional risks to the integrity of CSPs when assigning
using sterile syringes with sterile needles,
BUDs. The pre-administration storage duration
other administration devices, and other sterile
and temperature limits specified in the following
containers. The solution content of ampuls
subsections apply in the absence of direct sterility
should be passed through a sterile filter to re-
testing results that justify different limits for spe-
move any particles.
cific CSPs.
2. Simple aseptic measuring and transferring
with not more than three packages of manu-
Low-Risk Level CSPs
factured sterile products, including an infu-
sion or diluent solution to compound drug ad-
CSPs compounded under all the following con-
mixtures and nutritional solutions.
ditions are at a low risk of contamination.
Low-Risk Level CSPs with 12-Hour or Less Low-Risk Conditions
BUDIf the PEC is a CAI or CACI that does not
1. The CSPs are compounded with aseptic ma-
meet the requirements described in Placement of
nipulations entirely within ISO Class 5 (see
Primary Engineering Controls or is a laminar air-
Table 1) or better air quality using only sterile
flow workbench (LAFW) or a biological safety
ingredients, products, components, and
cabinet (BSC) that cannot be located within an
devices.
ISO Class 7 (see Table 1) buffer area, then only
2. The compounding involves only transfer,
low-risk level nonhazardous and radi-
measuring, and mixing manipulations using
opharmaceutical CSPs pursuant to a physicians
not more than three commercially manufac-
order for a specific patient may be prepared, and
tured packages of sterile products and not
administration of such CSPs shall commence
more than two entries into any one sterile
within 12 hours of preparation or as recommended
container or package (e.g., bag, vial) of sterile
in the manufacturers package insert, whichever is
product or administration container/device to
less. Low-risk level CSPs with a 12-hour or less
prepare the CSP.
BUD shall meet all of the following four criteria:
3. Manipulations are limited to aseptically open-
ing ampuls, penetrating disinfected stoppers 1. PECs (LAFWs, BSCs, CAIs, CACIs,) shall
on vials with sterile needles and syringes, and be certified and maintain ISO Class 5 (see Ta-
transferring sterile liquids in sterile syringes ble 1) as described in Facility Design and En-
to sterile administration devices, package con- vironmental Controls for exposure of critical
tainers of other sterile products, and con- sites and shall be in a segregated compound-
tainers for storage and dispensing. ing area restricted to sterile compounding ac-
tivities that minimize the risk of CSP 3. Review of all orders and packages of ingredi-
contamination. ents to ensure that the correct identity and
2. The segregated compounding area shall not amounts of ingredients were compounded.
be in a location that has unsealed windows or 4. Visual inspection of CSPs to ensure the ab-
doors that connect to the outdoors or high sence of particulate matter in solutions, the
traffic flow, or that is adjacent to construction absence of leakage from vials and bags, and
sites, warehouses, or food preparation. Note the accuracy and thoroughness of labeling.
that this list is not intended to be all
Media-Fill Test ProcedureThis test or an
inclusive.
equivalent test is performed at least annually by
3. Personnel shall follow the procedures de-
each person authorized to compound in a low-risk
scribed in Personnel Cleansing and Garbing
level environment under conditions that closely
and Additional Personnel Requirements prior
simulate the most challenging or stressful condi-
to compounding. Sinks should not be located
tions encountered during compounding of low-risk
adjacent to the ISO Class 5 (see Table 1)
level CSPs. Once begun, this test is completed
PEC. Sinks should be separated from the im-
without interruption. Example of test procedure:
mediate area of the ISO Class 5 (see Table 1)
within an ISO Class 5 (see Table 1) air quality en-
PEC device.
vironment, three sets of four 5-mL aliquots of ster-
4. The specifications in Cleaning and Disinfect-
ile SoybeanCasein Digest Medium (also known
ing the Sterile Compounding Areas, Person-
as trypticase soy broth or trypticase soy agar
nel Training and Competency Evaluation of
[TSA]) are transferred with the same sterile 10-mL
Garbing, Aseptic Work Practices and Clean-
syringe and vented needle combination into separ-
ing/Disinfection Procedures, and Viable and
ate sealed, empty, sterile 30-mL clear vials (i.e.,
Nonviable Environmental Sampling (ES)
four 5-mL aliquots into each of three 30-mL vials).
Testing shall be followed as described in the
Sterile adhesive seals are aseptically affixed to the
chapter.
rubber closures on the three filled vials, then the
Compounding personnel must recognize that the
vials are incubated at 20 to 25 or at 30 to 35
absence of an ISO Class 7 (see Table 1) buffer
for a minimum of 14 days. If two temperatures are
area environment in a general uncontrolled envi-
used for incubation of media-filled samples, then
ronment increases the potential of microbial con-
these filled containers should be incubated for at
tamination, and administration durations of
least 7 days at each temperature (see Microbiologi-
microbially contaminated CSPs exceeding a few
cal Evaluation of Clean Rooms and Other Con-
hours increase the potential for clinically signifi-
trolled Environments 1116). Inspect for micro-
cant microbial colonization, and thus for patient
bial growth over 14 days as described in Personnel
harm, especially in critically ill or immunocom-
Training and Competency Evaluation of Garbing,
promised patients.
Aseptic Work Practices and Cleaning/Disinfection
Quality AssuranceQuality assurance prac-
Procedures.
tices include, but are not limited to the following:
1. Routine disinfection and air quality testing of
Medium-Risk Level CSPs
the direct compounding environment to mini-
When CSPs are compounded aseptically under
mize microbial surface contamination and
Low-Risk Conditions and one or more of the fol-
maintain ISO Class 5 (see Table 1) air quality.
lowing conditions exists, such CSPs are at a med-
2. Visual confirmation that compounding per-
ium risk of contamination.
sonnel are properly donning and wearing ap-
Medium-Risk Conditions propriate items and types of protective gar-
ments, including eye protection and face 1. Multiple individual or small doses of sterile
masks. products are combined or pooled to prepare a
CSP that will be administered either to multi- vironment, six 100-mL aliquots of sterile
ple patients or to one patient on multiple SoybeanCasein Digest Medium are aseptically
occasions. transferred by gravity through separate tubing sets
2. The compounding process includes complex into separate evacuated sterile containers. The six
aseptic manipulations other than the single- containers are then arranged as three pairs, and a
volume transfer. sterile 10-mL syringe and 18-gauge needle combi-
3. The compounding process requires unusually nation is used to exchange two 5-mL aliquots of
long duration, such as that required to com- medium from one container to the other container
plete dissolution or homogeneous mixing. in the pair. For example, after a 5-mL aliquot from
4. For a medium-risk preparation, in the absence the first container is added to the second container
of passing a sterility test (see Sterility Tests in the pair, the second container is agitated for 10
71), the storage periods cannot exceed the seconds, then a 5-mL aliquot is removed and re-
following time periods: before administration, turned to the first container in the pair. The first
the CSPs are properly stored and are exposed container is then agitated for 10 seconds, and the
for not more than 30 hours at controlled room next 5-mL aliquot is transferred from it back to the
temperature (see General Notices and Re- second container in the pair. Following the two
quirements), for not more than 9 days at a 5-mL aliquot exchanges in each pair of containers,
cold temperature (see General Notices and a 5-mL aliquot of medium from each container is
Requirements), and for 45 days in solid frozen aseptically injected into a sealed, empty, sterile
state between 25 and 10. 10-mL clear vial, using a sterile 10-mL syringe
Examples of Medium-Risk Compounding and vented needle. Sterile adhesive seals are asep-
1. Compounding of total parenteral nutrition flu- tically affixed to the rubber closures on the three
ids using manual or automated devices during filled vials, then the vials are incubated at 20 to
which there are multiple injections, detach- 25 or at 30 to 35 for a minimum of 14 days. If
ments, and attachments of nutrient source two temperatures are used for incubation of media-
products to the device or machine to deliver filled samples, then these filled containers should
all nutritional components to a final sterile be incubated for at least 7 days at each temperature
container. (see Microbiological Evaluation of Clean Rooms
2. Filling of reservoirs of injection and infusion and Other Controlled Environments 1116). In-
devices with more than three sterile drug spect for microbial growth over 14 days as de-
products and evacuation of air from those res- scribed in Personnel Training and Competency
ervoirs before the filled device is dispensed. Evaluation of Garbing, Aseptic Work Practices
3. Transfer of volumes from multiple ampuls or and Cleaning/Disinfection Procedures.
vials into one or more final sterile containers.
Quality AssuranceQuality assurance proce-
High-Risk Level CSPs
dures for medium-risk level CSPs include all those
CSPs compounded under any of the following
for low-risk level CSPs, as well as a more chal-
conditions are either contaminated or at a high risk
lenging media-fill test passed annually or more
to become contaminated.
frequently.
High-Risk Conditions
Media-Fill Test ProcedureThis test or an
1. Nonsterile ingredients, including manufac- equivalent test is performed at least annually under
tured products not intended for sterile routes conditions that closely simulate the most challeng-
of administration (e.g., oral), are incorporated ing or stressful conditions encountered during
or a nonsterile device is employed before ter- compounding. Once begun, this test is completed
minal sterilization. without interruption. Example of test procedure:
within an ISO Class 5 (see Table 1) air quality en- 2. Any of the following are exposed to air qual-
ity worse than ISO Class 5 (see Table 1) for matter. Sterilization of high-risk level CSPs by fil-
more than 1 hour (see Immediate-Use tration shall be performed with a sterile 0.2-m or
CSPs): 0.22-m nominal pore size filter entirely within an
sterile contents of commercially manu- ISO Class 5 (see Table 1) or superior air quality
factured products, environment.
CSPs that lack effective antimicrobial
Examples of High-Risk Conditions
preservatives, and
1. Dissolving nonsterile bulk drug and nutrient
sterile surfaces of devices and containers
powders to make solutions that will be termi-
for the preparation, transfer, sterilization,
nally sterilized.
and packaging of CSPs.
2. Exposing the sterile ingredients and compo-
3. Compounding personnel are improperly
nents used to prepare and package CSPs to
garbed and gloved (see Personnel Cleansing
room air quality worse than ISO Class 5 (see
and Use of Barrier Protective Equipment).
Table 1) for more than 1 hour (see Immediate-
4. Nonsterile water-containing preparations are
Use CSPs).
stored for more than 6 hours before being
3. Measuring and mixing sterile ingredients in
sterilized.
nonsterile devices before sterilization is
5. It is assumed, and not verified by examination
performed.
of labeling and documentation from suppliers
4. Assuming, without appropriate evidence or
or by direct determination, that the chemical
direct determination, that packages of bulk in-
purity and content strength of ingredients
gredients contain at least 95% by weight of
meet their original or compendial specifica-
their active chemical moiety and have not
tions in unopened or in opened packages of
been contaminated or adulterated between
bulk ingredients (see Ingredient Selection
uses.
under Pharmaceutical CompoundingNon-
Quality AssuranceQuality assurance proce-
sterile Preparations 795).
dures for high-risk level CSPs include all those for
For a sterilized high-risk level preparation, in the
low-risk level CSPs. In addition, a media-fill test
absence of passing a sterility test, the storage pe-
that represents high-risk level compounding is per-
riods cannot exceed the following time periods:
formed semiannually by each person authorized to
before administration, the CSPs are properly
compound high-risk level CSPs.
stored and are exposed for not more than 24 hours
Media-Fill Test Procedure for CSPs Sterilized
at controlled room temperature (see General No-
by FiltrationThis test or an equivalent test is
tices and Requirements), for not more than 3 days
performed under conditions that closely simulate
at a cold temperature (see General Notices and Re-
the most challenging or stressful conditions en-
quirements), and for 45 days in solid frozen state
countered when compounding high-risk level
between 25 and 10. [NOTESterility tests for
CSPs. Once begun, this test is completed without
autoclaved CSPs are not required unless they are
interruption. Example of test procedure (in the fol-
prepared in batches of more than 25 units.]
lowing sequence):
All nonsterile measuring, mixing, and purifying
1. Dissolve 3g of nonsterile commercially avail-
devices are rinsed thoroughly with sterile, pyro-
able SoybeanCasein Digest Medium in 100
gen-free water, and then thoroughly drained or
mL of nonbacteriostatic water to make a 3%
dried immediately before use for high-risk com-
nonsterile solution.
pounding. All high-risk level CSP solutions sub-
jected to terminal sterilization are prefiltered by 2. Draw 25 mL of the medium into each of three
passing through a filter with a nominal pore size 30-mL sterile syringes. Transfer 5 mL from
not larger than 1.2 m preceding or during filling each syringe into separate sterile 10-mL vials.
into their final containers to remove particulate These vials are the positive controls to gener-
ate exponential microbial growth, which is in- Media-Fill Challenge TestingThe skill of
dicated by visible turbidity upon incubation. personnel to aseptically prepare CSPs may be
evaluated using sterile fluid bacterial culture me-
3. Under aseptic conditions and using aseptic
dia-fill verification
3
(i.e., sterile bacterial culture
techniques, affix a sterile 0.2-m or 0.22-m
medium transfer via a sterile syringe and needle).
nominal pore size filter unit and a 20-gauge
Media-fill testing is used to assess the quality of
needle to each syringe. Inject the next 10 mL
the aseptic skill of compounding personnel. Me-
from each syringe into three separate 10-mL
dia-fill tests represent the most challenging or
sterile vials. Repeat the process for three more
stressful conditions actually encountered by the
vials. Label all vials, affix sterile adhesive
personnel being evaluated when they prepare par-
seals to the closure of the nine vials, and incu-
ticular risk level CSPs and when sterilizing high-
bate them at 20 to 25 or at 30 to 35 for a
risk level CSPs. Media-fill challenge tests that
minimum of 14 days. If two temperatures are
simulate high-risk level compounding are also
used for incubation of media-filled samples,
used to verify the capability of the compounding
then these filled containers should be incu-
environment and process to produce a sterile
bated for at least 7 days at each temperature
preparation.
(see Microbiological Evaluation of Clean
Rooms and Other Controlled Environments Commercially available sterile fluid culture me-
1116). Inspect for microbial growth over 14 dia, such as SoybeanCasein Digest Medium (see
days as described in Personnel Training and Sterility Tests 71), shall be able to promote expo-
Competency Evaluation of Garbing, Aseptic nential colonization of bacteria that are most likely
Work Practices and Cleaning/Disinfection to be transmitted to CSPs from the compounding
Procedures. personnel and environment. Media-filled vials are
generally incubated at 20 to 25 or at 30 to 35
for a minimum of 14 days. If two temperatures are
PERSONNEL TRAINING AND
used for incubation of media-filled samples, then
EVALUATION IN ASEPTIC
these filled containers should be incubated for at
MANIPULATION SKILLS
least 7 days at each temperature (see Microbiologi-
Personnel who prepare CSPs shall be trained
conscientiously and skillfully by expert personnel
trolled Environments 1116). Failure is indicated
and through audiovideo instructional sources and
by visible turbidity in the medium on or before 14
professional publications in the theoretical princi-
days.
ples and practical skills of aseptic manipulations
and in achieving and maintaining ISO Class 5 (see
IMMEDIATE-USE CSPs
Table 1) environmental conditions before they be-
gin to prepare CSPs. Compounding personnel shall The immediate-use provision is intended only
perform didactic review and pass written and me- for those situations where there is a need for emer-
dia-fill testing of aseptic manipulative skills ini- gency or immediate patient administration of a
tially, at least annually thereafter for low- and CSP. Such situations may include cardiopulmo-
medium-risk level compounding, and semiannu- nary resuscitation, emergency room treatment,
ally for high-risk level compounding. Compound- preparation of diagnostic agents, or critical therapy
ing personnel who fail written tests or whose me- where the preparation of the CSP under conditions
dia-fill test vials result in gross microbial described for Low-Risk Level CSPs subjects the
colonization shall be immediately re-instructed patient to additional risk due to delays in therapy.
and re-evaluated by expert compounding person- Immediate-use CSPs are not intended for storage
nel to ensure correction of all aseptic practice for anticipated needs or batch compounding. Prep-
deficiencies. arations that are medium-risk level and high-risk
level CSPs shall not be prepared as immediate-use significant microbial colonization and thus for pa-
CSPs. tient harm, especially in critically ill or immu-
Immediate-use CSPs are exempt from the re- nocompromised patients.
quirements described for Low-Risk Level CSPs
SINGLE-DOSE AND MULTIPLE-DOSE
only when all of the following criteria are met:
CONTAINERS
1. The compounding process involves simple
transfer of not more than three commercially
Opened or needle-punctured single-dose con-
manufactured packages of sterile nonhazard-
tainers, such as bags, bottles, syringes, and vials of
ous products or diagnostic radiopharmaceuti-
sterile products and CSPs shall be used within 1
cal products from the manufacturers original
hour if opened in worse than ISO Class 5 (see Ta-
containers and not more than two entries into
ble 1) air quality (see Immediate-Use CSPs), and
any one container or package (e.g., bag, vial)
any remaining contents must be discarded. Single-
of sterile infusion solution or administration
dose vials exposed to ISO Class 5 (see Table 1) or
container/device. For example, anti-neoplas-
cleaner air may be used up to 6 hours after initial
tics shall not be prepared as immediate-use
needle puncture. Opened single-dose ampuls shall
CSPs because they are hazardous drugs.
not be stored for any time period. Multiple-dose
2. Unless required for the preparation, the com-
containers (e.g., vials) are formulated for removal
pounding procedure is a continuous process
of portions on multiple occasions because they
not to exceed 1 hour.
usually contain antimicrobial preservatives. The
3. During preparation, aseptic technique is fol-
BUD after initially entering or opening (e.g., nee-
lowed and, if not immediately administered,
dle-punctured) multiple-dose containers is 28 days
the finished CSP is under continuous supervi-
(see Antimicrobial Effectiveness Testing 51) un-
sion to minimize the potential for contact with
less otherwise specified by the manufacturer.
nonsterile surfaces, introduction of particulate
matter or biological fluids, mix-ups with other
HAZARDOUS DRUGS AS CSPs
CSPs, and direct contact of outside surfaces.
4. Administration begins not later than 1 hour Although the potential therapeutic benefits of
following the start of the preparation of the compounded sterile hazardous drug preparations
CSP. generally outweigh the risks of their adverse ef-
5. Unless immediately and completely adminis- fects in ill patients, exposed healthcare workers
tered by the person who prepared it or im- risk similar adverse effects with no therapeutic
mediate and complete administration is wit- benefit. Occupational exposure to hazardous drugs
nessed by the preparer, the CSP shall bear a can result in (1) acute effects, such as skin rashes;
label listing patient identification information, (2) chronic effects, including adverse reproductive
the names and amounts of all ingredients, the events; and (3) possibly cancer (see Appendix A of
name or initials of the person who prepared NIOSH Publication no. 2004-165).
the CSP, and the exact 1-hour BUD and time. Hazardous drugs shall be prepared for adminis-
6. If administration has not begun within 1 hour tration only under conditions that protect the
following the start of preparing the CSP, the healthcare workers and other personnel in the
CSP shall be promptly, properly, and safely preparation and storage areas. Hazardous drugs
discarded. shall be stored separately from other inventory in a
Compounding in worse than ISO Class 5 (see manner to prevent contamination and personnel
Table 1) conditions increases the likelihood of mi- exposure. Many hazardous drugs have sufficient
crobial contamination, and administration dura- vapor pressures that allow volatilization at room
tions of microbially contaminated CSPs exceeding temperature; thus storage is preferably within a
a few hours increase the potential for clinically containment area such as a negative pressure
room. The storage area should have sufficient gen- cause of their inherent closed system process. In
eral exhaust ventilation, at least 12 air changes per facilities that prepare a low volume of hazardous
hour (ACPH)
4
to dilute and remove any airborne drugs, the use of two tiers of containment (e.g.,
contaminants. CSTD within a BSC or CACI that is located in a
non-negative pressure room) is acceptable. Hazardous drugs shall be handled with caution at
Appropriate personnel protective equipment all times using appropriate chemotherapy gloves
(PPE) shall be worn when compounding in a BSC during receiving, distribution, stocking, inventory-
or CACI and when using CSTD devices. PPE ing, preparation for administration, and disposal.
should include gowns, face masks, eye protection, Hazardous drugs shall be prepared in an ISO Class
hair covers, shoe covers or dedicated shoes, double 5 (see Table 1) environment with protective engi-
gloving with sterile chemo-type gloves, and com- neering controls in place and following aseptic
pliance with manufacturers recommendations practices specified for the appropriate contamina-
when using a CACI. tion risk levels defined in this chapter. Access
All personnel who compound hazardous drugs shall be limited to areas where drugs are stored
shall be fully trained in the storage, handling, and and prepared to protect persons not involved in
disposal of these drugs. This training shall occur drug preparation.
prior to preparing or handling hazardous CSPs,
All hazardous drugs shall be prepared in a BSC
5
and its effectiveness shall be verified by testing
or a CACI that meets or exceeds the standards for
specific hazardous drugs preparation techniques.
CACI in this chapter. The ISO Class 5 (see Table
Such verification shall be documented for each
1) BSC or CACI shall be placed in an ISO Class 7
person at least annually. This training shall include
(seeTable 1) area that is physically separated (i.e.,
didactic overview of hazardous drugs, including
a different area from other preparation areas) and
mutagenic, teratogenic, and carcinogenic proper-
optimally has not less than 0.01-inch water column
ties, and it shall include ongoing training for each
negative pressure to adjacent positive pressure ISO
new hazardous drug that enters the marketplace.
Class 7 (see Table 1) or better ante-areas, thus pro-
Compounding personnel of reproductive capability
viding inward airflow to contain any airborne
shall confirm in writing that they understand the
drug. A pressure indicator shall be installed that
risks of handling hazardous drugs. The training
can be readily monitored for correct room pressur-
shall include at least the following: (1) safe aseptic
ization. The BSC and CACI optimally should be
manipulation practices; (2) negative pressure tech-
100% vented to the outside air through HEPA
niques when utilizing a BSC or CACI; (3) correct
filtration.
use of CSTD devices; (4) containment, cleanup,
If a CACI that meets the requirements of this
and disposal procedures for breakages and spills;
chapter is used outside of a buffer area, the com-
and (5) treatment of personnel contact and inhala-
pounding area shall maintain a minimum negative
tion exposure.
pressure of 0.01-inch water column and have a
NOTEBecause standards of assay and unac-
minimum of 12 ACPHs.
ceptable quantities of contamination of each drug
When closed-system vial-transfer devices
have not been established in the literature, the fol-
(CSTDs) (i.e., vial-transfer systems that allow no
lowing paragraph is a recommendation only. Fu-
venting or exposure of hazardous substance to the
ture standards will be adopted as these assay
environment) are used, they shall be used within
methods are developed and proven.
the ISO Class 5 (see Table 1) environment of a
In order to ensure containment, especially in op-
BSC or CACI. The use of a CSTD is preferred be-
erations preparing large volumes of hazardous
4
Guidelines for Environmental Infection Control in Health-Care Fa-
drugs, environmental sampling to detect uncon- cilities, Recommendations of CDC and the Healthcare Infection
Control Practices Advisory Committee (HICPAC), MMWR, vol.
tained hazardous drugs should be performed rou-
52, no. RR-10, J une 6, 2003, figure 3, pg. 12.
5
NSF/ANSI 49. tinely (e.g., initially as a benchmark and at least
every 6 months or more often as needed to verify or not more than 30 mL taken from a multiple-
containment). This sampling should include sur- dose container (see Injections 1) shall be desig-
face wipe sampling of the working area of BSCs nated as, and conform to, the standards for Low-
and CACIs; counter tops where finished prepara- Risk Level CSPs.
tions are placed; areas adjacent to BSCs and These radiopharmaceuticals shall be com-
CACIs, including the floor directly under the pounded using appropriately shielded vials and
working area; and patient administration areas. syringes in a properly functioning and certified
Common marker hazardous drugs that can be as- ISO Class 5 (see Table 1) PEC located in an ISO
sayed include cyclophosphamide, ifosfamide, Class 8 (see Table 1) or cleaner air environment to
methotrexate, and fluorouracil. If any measurable permit compliance with special handling, shield-
contamination (cyclophosphamide levels greater ing, and negative air flow requirements.
than 1.00 ng per cm
2
have been found to cause hu- Radiopharmaceutical vials designed for multi-
man uptake) is found by any of these quality assur- use, compounded with technetium-99m, exposed
ance procedures, practitioners shall make the deci- to ISO Class 5 (see Table 1) environment, and
sion to identify, document, and contain the cause punctured by needles with no direct contact con-
of contamination. Such action may include retrain- tamination may be used up to the time indicated by
ing, thorough cleaning (utilizing high-pH soap and manufacturers recommendations. Storage and
water), and improving engineering controls. Ex- transport of properly shielded vials of radi-
amples of improving engineering controls are (1) opharmaceutical CSPs may occur in a limited ac-
venting BSCs or CACIs 100% to the outside, (2) cess ambient environment without a specific ISO
implementing a CSTD, or (3) re-assessing types of class designation.
BSCs or CACIs. Technetium-99m/molybdenum-99generator sys-
Disposal of all hazardous drug wastes shall com- tems shall be stored and eluted (operated) under
ply with all applicable federal and state regu- conditions recommended by manufacturers and
lations. All personnel who perform routine custo- applicable state and federal regulations. Such gen-
dial waste removal and cleaning activities in erator systems shall be eluted in an ISO Class 8
storage and preparation areas for hazardous drugs (seeTable 1) or cleaner air environment to permit
shall be trained in appropriate procedures to pro- special handling, shielding, and air flow require-
tect themselves and prevent contamination. ments. To limit acute and chronic radiation expo-
sure of inspecting personnel to a level that is as
RADIOPHARMACEUTICALS AS CSPs
low as reasonably achievable (ALARA), direct
visual inspection of radiopharmaceutical CSPs
In the case of production of radiopharmaceuti-
containing high concentrations of doses of radioac-
cals for positron emission tomography (PET), gen-
tivity shall be conducted in accordance with
eral test chapter Radiopharmaceuticals for Posi-
ALARA.
tron Emission TomographyCompounding 823
Radiopharmaceuticals prepared as Low-Risk
supersedes this chapter. Upon release of a PET
Level CSPs with 12-Hour or Less BUD shall be
radiopharmaceutical as a finished drug product
prepared in a segregated compounding area. A line
from a production facility, the further handling,
of demarcation defining the segregated compound-
manipulation, or use of the product will be consid-
ing area shall be established. Materials and garb
ered compounding, and the content of this section
exposed in a patient care and treatment area shall
and chapter is applicable.
not cross a line of demarcation into the segregated
For the purposes of this chapter, radi-
compounding area.
opharmaceuticals compounded from sterile com-
ponents in closed sterile containers and with a vol-
ume of 100 mL or less for a single-dose injection
ALLERGEN EXTRACTS AS CSPs for at least 10 seconds and allowed to dry be-
fore they are used to compound allergen ex-
Allergen extracts as CSPs are single-dose and
tracts as CSPs.
multiple-dose intradermal or subcutaneous injec-
9. The aseptic compounding manipulations min-
tions that are prepared by specially trained physi-
imize direct contact contamination (e.g., from
cians and personnel under their direct supervision.
glove fingertips, blood, nasal and oral secre-
Allergen extracts as CSPs are not subject to the
tions, shed skin and cosmetics, other nonster-
personnel, environmental, and storage require-
ile materials) of critical sites (e.g., needles,
ments for all CSP Microbial Contamination Risk
opened ampuls, vial stoppers).
Levels in this chapter only when all of the follow-
10. The label of each multiple-dose vial (MDV)
ing criteria are met:
of allergen extracts as CSPs lists the name of
1. The compounding process involves simple
one specific patient and a BUD and storage
transfer via sterile needles and syringes of
temperature range that is assigned based on
commercial sterile allergen products and ap-
manufacturers recommendations or peer-re-
propriate sterile added substances (e.g., glyc-
viewed publications.
erin, phenol in sodium chloride injection).
11. Single-dose allergen extracts as CSPs shall
2. All allergen extracts as CSPs shall contain ap-
not be stored for subsequent additional use.
propriate substances in effective concentra-
Personnel who compound allergen extracts as
tions to prevent the growth of microorgan-
CSPs must be aware of greater potential risk of
isms. Nonpreserved allergen extracts shall
microbial and foreign material contamination
comply with the appropriate CSP risk level
when allergen extracts as CSPs are compounded in
requirements in the chapter.
compliance with the foregoing criteria instead of
3. Before beginning compounding activities,
the more rigorous standards in this chapter for CSP
personnel perform a thorough hand-cleansing
Microbial Contamination Risk Levels. Although
procedure by removing debris from under fin-
contaminated allergen extracts as CSPs can pose
gernails using a nail cleaner under running
health risks to patients when they are injected in-
warm water followed by vigorous hand and
tradermally or subcutaneously, these risks are sub-
arm washing to the elbows for at least 30 sec-
stantially greater if the extract is inadvertently in-
onds with either nonantimicrobial or antimi-
jected intravenously.
crobial soap and water.
4. Compounding personnel don hair covers, fa-
VERIFICATION OF COMPOUNDING
cial hair covers, gowns, and face masks.
ACCURACY AND STERILITY
5. Compounding personnel perform antiseptic
hand cleansing with an alcohol-based surgical
The compounding procedures and sterilization
hand scrub with persistent activity.
methods for CSPs correspond to correctly de-
6. Compounding personnel don powder-free
signed and verified written documentation in the
sterile gloves that are compatible with sterile
compounding facility. Verification requires
70% isopropyl alcohol (IPA) before begin-
planned testing, monitoring, and documentation to
ning compounding manipulations.
demonstrate adherence to environmental quality
7. Compounding personnel disinfect their gloves requirements, personnel practices, and procedures
intermittently with sterile 70% IPA when pre- critical to achieving and maintaining sterility, ac-
paring multiple allergen extracts as CSPs. curacy, and purity of finished CSPs. For example,
8. Ampul necks and vial stoppers on packages of sterility testing (see Test for Sterility of the Prod-
manufactured sterile ingredients are disin- uct To Be Examined under Sterility Tests 71)
fected by careful wiping with sterile 70% IPA may be applied to specimens of low- and medium-
swabs to ensure that the critical sites are wet risk level CSPs, and standard self-contained bio-
logical indicators (BI) shall be added to nondis- Sterility Assurance of Compendial Articles 1211)
pensable specimens of high-risk level CSPs before both sterilizes and maintains the strength, purity,
terminal sterilization for subsequent evaluation to quality, and packaging integrity of CSPs. The se-
determine whether the sterilization cycle was ade- lected sterilization process is obtained from experi-
quate (see Biological Indicators for Sterilization ence and appropriate information sources (e.g., see
1035). Packaged and labeled CSPs shall be visu- Sterilization and Sterility Assurance of Com-
ally inspected for physical integrity and expected pendial Articles 1211)and, preferably, verified
appearance, including final fill amount. The accu- wherever possibleto achieve sterility in the par-
racy of identities, concentrations, amounts, and pu- ticular CSPs. General guidelines for matching
rities of ingredients in CSPs shall be confirmed by CSPs and components to appropriate sterilization
reviewing labels on packages, observing and docu- methods include the following:
menting correct measurements with approved and 1. CSPs have been ascertained to remain physi-
correctly standardized devices, and reviewing in- cally and chemically stable when subjected to
formation in labeling and certificates of analysis the selected sterilization method.
provided by suppliers. When the correct identity,
2. Glass and metal devices may be covered
purity, strength, and sterility of ingredients and
tightly with aluminum foil, then exposed to
components of CSPs cannot be confirmed (in
dry heat in an oven at a mean temperature of
cases of, for example, unlabeled syringes, opened
250 for 30 minutes to achieve sterility and
ampuls, punctured stoppers of vials and bags, con-
depyrogenation (see Dry-Heat Sterilization
tainers of ingredients with incomplete labeling),
under Sterilization and Sterility Assurance of
such ingredients and components shall be dis-
Compendial Articles 1211 and Bacterial En-
carded immediately.
dotoxins Test 85). Such items are either used
Some individual ingredients, such as bulk drug immediately or stored until use in an environ-
substances, are not labeled with expiration dates ment suitable for compounding Low-Risk
when they are stable indefinitely in their commer- Level CSPs and Medium-Risk Level CSPs.
cial packages under their labeled storage condi-
3. Personnel ascertain from appropriate informa-
tions. However, despite retaining full chemical sta-
tion sources that the sterile microporous
bility, such ingredients may gain or lose moisture
membrane filter used to sterilize CSP solu-
during storage and use. Changes in moisture con-
tions, during either compounding or adminis-
tent may require testing (see Loss on Drying 731)
tration, is chemically and physically compati-
to determine the correct amount to weigh for accu-
ble with the CSP.
rate content of active chemical moieties in CSPs
(see Pharmaceutical Calculations in Prescription
STERILIZATION OF HIGH-RISK LEVEL CSPs BY
Compounding 1160).
FILTRATION
Although not required, a quantitative stability-in-
Commercially available sterile filters shall be ap-
dicating chemical assay is recommended to ensure
proved for human-use applications in sterilizing
compounding accuracy of CSPs, especially those
pharmaceutical fluids. Sterile filters used to steril-
that contain drug ingredients with a narrow thera-
ize CSPs shall be pyrogen free and have a nominal
peutic plasma concentration range.
pore size of 0.2 or 0.22 m. They shall be certified
by the manufacturer to retain at least 10
7
microor-
Sterilization Methods
ganisms of a strain of Brevundimonas (Pseudomo-
The licensed healthcare professionals who super- nas) diminuta on each square centimeter of up-
vise compounding shall be responsible for deter- stream filter surface area under conditions similar
mining that the selected sterilization method (see to those in which the CSPs will be sterilized (see
Methods of Sterilization under Sterilization and High-Risk Conditions in High-Risk Level CSPs).
The compounding supervisor shall ensure, di- quired for the material to reach 121 before the
rectly or from appropriate documentation, that the sterilization exposure duration is timed.
filters are chemically and physically stable at the
Not directly exposing items to pressurized steam
pressure and temperature conditions to be used,
may result in survival of microbial organisms and
that they have enough capacity to filter the re-
spores. Before their sterilization, plastic, glass, and
quired volumes, and that they will achieve sterility
metal devices are tightly wrapped in low-particle-
and maintain prefiltration pharmaceutical quality,
shedding paper or fabrics or sealed in envelopes
including strength of ingredients of the specific
that prevent poststerilization microbial penetration.
CSP. The filter dimensions and liquid material to
Immediately before filling ampuls and vials that
be sterile-filtered shall permit the sterilization pro-
will be steam sterilized, solutions are passed
cess to be completed rapidly, without the replace-
through a filter having a nominal pore size not
ment of the filter during the process. When CSPs
larger than 1.2 m for removal of particulate mat-
are known to contain excessive particulate matter,
ter. Sealed containers shall be able to generate
a prefilter of larger nominal pore size membrane is
steam internally; thus, stoppered and crimped
placed upstream from the sterilizing filter to re-
empty vials shall contain a small amount of mois-
move gross particulate contaminants in order to
ture to generate steam.
maximize the efficiency of the sterilizing filter.
The description of steam sterilization conditions
and duration for specific CSPs shall be included in
Filter units used to sterilize CSPs shall also be
written documentation in the compounding facil-
subjected to manufacturers recommended integ-
ity. The effectiveness of steam sterilization shall
rity test, such as the bubble point test.
be verified using appropriate BIs of Bacillus
Compounding personnel shall ascertain that se-
stearothermophilus (see Biological Indicators
lected filters will achieve sterilization of the partic-
1035) and other confirmation methods such as
ular CSPs being sterilized. Large deviations from
temperature-sensing devices (see Sterilization and
usual or expected chemical and physical properties
Sterility Assurance of Compendial Articles 1211
of CSPs (e.g., water-miscible alcohols) may cause
and Sterility Tests 71).
undetectable damage to filter integrity and shrink-
age of microorganisms to sizes smaller than filter
STERILIZATION OF HIGH-RISK LEVEL CSPs BY DRY
nominal pore size.
HEAT
Dry heat sterilization is usually done as a batch
STERILIZATION OF HIGH-RISK LEVEL CSPs BY
process in an oven designed for sterilization.
STEAM
Heated filtered air shall be evenly distributed
The process of thermal sterilization employing throughout the chamber by a blower device. The
saturated steam under pressure, or autoclaving, is oven should be equipped with a system for con-
the preferred method to terminally sterilize aque- trolling temperature and exposure period. Steriliza-
ous preparations that have been verified to main- tion by dry heat requires higher temperatures and
tain their full chemical and physical stability under longer exposure times than does sterilization by
the conditions employed (see Steam Sterilization steam. Dry heat shall be used only for those mate-
under Sterilization and Sterility Assurance of Com- rials that cannot be sterilized by steam, when ei-
pendial Articles 1211). To achieve sterility, all ther the moisture would damage the material or the
materials are to be exposed to steam at 121 under material is impermeable. During sterilization, suf-
a pressure of about 1 atmosphere or 15 psi for the ficient space shall be left between materials to al-
duration verified by testing to achieve sterility of low for good circulation of the hot air. The de-
the items, which is usually 20 to 60 minutes for scription of dry heat sterilization conditions and
CSPs. An allowance shall be made for the time re- duration for specific CSPs shall be included in
written documentation in the compounding facil- Exposure of Critical Sites
ity. The effectiveness of dry heat sterilization shall
Maintaining the sterility and cleanliness (i.e.,
be verified using appropriate BIs of Bacillus sub-
freedom from sterile foreign materials) of critical
tilis (see Biological Indicators 1035) and other
sites is a primary safeguard for CSPs. Critical sites
confirmation methods such as temperature-sensing
are locations that include any component or fluid
devices (see Sterilization and Sterility Assurance
pathway surfaces (e.g., vial septa, injection ports,
of Compendial Articles 1211 and Sterility Tests
beakers) or openings (e.g., opened ampuls, needle
71). [NOTEDry heat sterilization may be per-
hubs) exposed and at risk of direct contact with air
formed at a lower temperature than may be effec-
(e.g., ambient room or HEPA filtered), moisture
tive for depyrogenation].
(e.g., oral and mucosal secretions), or touch con-
tamination. The risk of, or potential for, critical
Depyrogenation by Dry Heat
sites to be contaminated with microorganisms and
Dry heat depyrogenation shall be used to render
foreign matter increases with increasing exposed
glassware or containers such as vials free from py-
area of the critical sites, the density or concentra-
rogens as well as viable microbes. A typical cycle
tion of contaminants, and exposure duration to
would be 30 minutes at 250. The description of
worse than ISO Class 5 (see Table 1) air. Exam-
the dry heat depyrogenation cycle and duration for
ples include an opened ampul or vial stopper on a
specific load items shall be included in written
10-mL or larger vial or an injection port on a pack-
documentation in the compounding facility. The
age of intravenous solution having an area larger
effectiveness of the dry heat depyrogenation cycle
than the point of a needle or the tip of a syringe.
shall be verified using endotoxin challenge vials
The nature of a critical site also affects the risk
(ECVs). The bacterial endotoxin test should be
of contamination. The relatively rough, permeable
performed on the ECVs to verify that the cycle is
surface of an elastomeric closure retains microor-
capable of achieving a 3-log reduction in endo-
ganisms and other contaminants after swabbing
toxin (see Sterilization and Sterility Assurance of
with a sterile 70% IPA pad more readily than does
Compendial Articles 1211 and Bacterial Endo-
the smoother glass surface of the neck of an am-
toxins Test 85).
pul. Therefore, the surface disinfection can be ex-
pected to be more effective for an ampul.
ENVIRONMENTAL QUALITY AND
Protection of critical sites by precluding physical
CONTROL
contact and airborne contamination shall be given
the highest priority in sterile compounding prac-
Achieving and maintaining sterility and overall
tice. Airborne contaminants, especially those gen-
freedom from contamination of a CSP is depend-
erated by sterile compounding personnel, are much
ent on the quality status of the components incor-
more likely to reach critical sites than are contami-
porated, the process utilized, personnel perform-
nants that are adhering to the floor or other sur-
ance, and the environmental conditions under
faces below the work level. Furthermore, large and
which the process is performed. The standards re-
high-density particles that are generated and intro-
quired for the environmental conditions depend on
duced by compounding manipulations and person-
the amount of exposure of the CSP to the immedi-
nel have the potential to settle on critical sites even
ate environment anticipated during processing.
when those critical sites are exposed within ISO
The quality and control of environmental condi-
Class 5 (see Table 1) air.
tions for each risk level of operation are explained
in this section. In addition, operations using non-
sterile components require the use of a method of
preparation designed to produce a sterile
preparation.
ISO Class 5 Air Sources, Buffer Areas, and categorized as low-, medium-, and high-risk level.
Ante-Areas The quality of the environmental air increases with
movement from the outer boundary to the direct
The most common sources of ISO Class 5 (see
compounding area (DCA). Placement of devices in
Table 1) air quality for exposure of critical sites
ante-areas and buffer areas is dictated by their ef-
are horizontal and vertical LAFWs, CAIs, and
fect on the designated environmental quality of at-
CACIs. A clean room (see Microbiological Evalu-
mospheres and surfaces, which shall be verified by
ation of Clean Rooms and Other Controlled Envi-
monitoring (see Viable and Nonviable Environ-
ronments 1116) is a compounding environment
mental Sampling (ES) Testing). It is the responsi-
that is supplied with HEPA or HEPA-filtered air
bility of each compounding facility to ensure that
that meets ISO Class 7 (see Table 1), the access to
each source of ISO Class 5 (see Table 1) environ-
which is limited to personnel trained and author-
ment for exposure of critical sites and
ized to perform sterile compounding and facility
sterilization by filtration is properly located, oper-
cleaning. A buffer area is an area that provides at
ated, maintained, monitored, and verified.
least ISO Class 7 (see Table 1) air quality.
Figure 1 is a conceptual representation of the
placement of an ISO Class 5 (see Table 1) PEC in
a segregated compounding area used for low-risk
level CSPs with 12-hour or less BUD. This plan
depicts the most critical operation area located
within the PEC in a designated area (see definition
of Segregated Compounding Area) separated from
activities not essential to the preparation of CSPs.
Placement of devices (e.g., computers, printers)
and objects (e.g., carts, cabinets) that are not es-
sential to compounding in the segregated area
should be restricted or limited, depending on their
Figure 2. Conceptual representation of the arrangement of a facil-
ity for preparation of CSPs categorized as low-, medium-, and
effect on air quality in the ISO Class 5 (see Table
high-risk level.
1) PEC.
Placement of devices (e.g., computers, printers)
and objects (e.g., carts, cabinets) that are not es-
sential to compounding in buffer areas is dictated
by their effect on the required environmental qual-
ity of air atmospheres and surfaces, which shall be
verified by monitoring (see Viable and Nonviable
Environmental Sampling (ES) Testing). It is the re-
sponsibility of each compounding facility to en-
sure that each source of ISO Class 5 (see Table 1)
environment for exposure of critical sites and ster-
ilization by filtration is properly located, operated,
maintained, monitored, and verified.
Figure 1. Conceptual representation of the placement of an ISO
Class 5 PEC in a segregated compounding area used for low-risk
Facility Design and Environmental Controls
level CSPs with 12-hour or less BUD.
Figure 2 is a conceptual representation of the ar- Compounding facilities are physically designed
rangement of a facility for preparation of CSPs and environmentally controlled to minimize air-
borne contamination from contacting critical sites. compounding activities utilized during the prepa-
These facilities shall also provide a comfortable ration of the CSPs. The CSP work environment is
and well-lighted working environment, which typi- designed to have the cleanest work surfaces (PEC)
cally includes a temperature of 20 or cooler, to located in a buffer area. The buffer area shall
maintain comfortable conditions for compounding maintain at least ISO Class 7 (see Table 1) condi-
personnel to perform flawlessly when attired in the tions for 0.5-m and larger particles under dy-
required aseptic compounding garb. PECs typi- namic operating conditions. The room shall be
cally include, but are not limited to, LAFWs, segregated from surrounding, unclassified spaces
BSCs, CAIs, and CACIs, which provide an ISO to reduce the risk of contaminants being blown,
Class 5 (see Table 1) environment for the exposure dragged, or otherwise introduced into the filtered
of critical sites. PECs shall maintain ISO Class 5 unidirectional airflow environment, and this segre-
(seeTable 1) or better conditions for 0.5-m parti- gation shall be continuously monitored. For rooms
cles (dynamic operating conditions) while com- providing a physical separation through the use of
pounding CSPs. Secondary engineering controls walls, doors, and pass-throughs, a minimum differ-
such as buffer areas and ante-areas generally serve ential positive pressure of 0.02- to 0.05-inch water
as a core for the location of the PEC. Buffer areas column is required. For buffer areas not physically
are designed to maintain at least ISO Class 7 (see separated from the ante-areas, the principle of dis-
Table 1) conditions for 0.5-m particles under dy- placement airflow shall be employed. This concept
namic conditions and ISO Class 8 (see Table 1) utilizes a low pressure differential, high airflow
conditions for 0.5-m and larger particles under principle. Using displacement airflow typically re-
dynamic conditions for the ante-areas. Airborne quires an air velocity of 40 ft per minute or more
contamination control is achieved in the PEC from the buffer area across the line of demarcation
through the use of HEPA filters. The airflow in the into the ante-area.
PEC shall be unidirectional (laminar flow), and be-
The displacement concept shall not be used for
cause of the particle collection efficiency of the fil-
high-risk compounding.
6
The PEC shall be placed
ter, the first air at the face of the filter is, for the
within a buffer area in such a manner as to avoid
purposes of aseptic compounding, free from air-
conditions that could adversely affect their opera-
borne particulate contamination. HEPA-filtered air
tion. For example, strong air currents from opened
shall be supplied in critical areas (ISO Class 5, see
doors, personnel traffic, or air streams from the
Table 1) at a velocity sufficient to sweep particles
HVAC systems can disrupt the unidirectional air-
away from the compounding area and maintain
flow in open-faced workbenches. The operators
unidirectional airflow during operations. Proper
may also create disruptions in airflow by their own
design and control prevents turbulence and stag-
movements and by the placement of objects onto
nant air in the critical area. In situ air pattern anal-
the work surface. The PEC shall be placed out of
ysis via smoke studies shall be conducted at the
the traffic flow and in a manner to avoid disruption
critical area to demonstrate unidirectional airflow
from the HVAC system and room cross-drafts.
and sweeping action over and away from the prod-
Room air exchanges are typically expressed as
uct under dynamic conditions.
ACPHs. Adequate HEPA-filtered airflow supplied
The principles of HEPA-filtered unidirectional
to the buffer area and ante-area is required to
airflow in the work environment shall be under-
maintain cleanliness classification during opera-
stood and practiced in the compounding process in
tional activity through the number of ACPHs. Fac-
order to achieve the desired environmental condi-
tors that should be considered when determining
tions. Policies and procedures for maintaining and
air-change requirements include number of per-
working within the PEC area shall be written and
6
ISO 14644-4: 2001 Cleanrooms and associated controlled envi-
followed. The policies and procedures will be de-
ronmentsDesign, construction, and start-up, Case Postale 56,
termined by the scope and risk levels of the aseptic CH-1211 Geneve 20, Switzerland, tel. +41 22 749 01 11.
sonnel working in the room and compounding mulate. The surfaces shall be resistant to damage
processes that generate particulates, as well as by disinfectant agents. J unctures of ceilings to
temperature effects. An ISO Class 7 (see Table 1) walls shall be coved or caulked to avoid cracks
buffer area and ante-area supplied with HEPA-fil- and crevices where dirt can accumulate. If ceilings
tered air shall receive an ACPH of not less than consist of inlaid panels, the panels shall be impreg-
30. The PEC is a good augmentation to generating nated with a polymer to render them impervious
air changes in the air supply of an area but cannot and hydrophobic, and they shall be caulked around
be the sole source of HEPA-filtered air. If the area each perimeter to seal them to the support frame.
has an ISO Class 5 (see Table 1) recirculating de- Walls may be constructed of flexible material
vice, a minimum of 15 ACPHs through the area (e.g., heavy gauge polymer), panels locked to-
supply HEPA filters is adequate, providing the gether and sealed, or of epoxy-coated gypsum
combined ACPH is not less than 30. More air board. Preferably, floors are overlaid with wide
changes may be required, depending on the num- sheet vinyl flooring with heat-welded seams and
ber of personnel and processes. HEPA-filtered coving to the sidewall. Dust-collecting overhangs,
supply air shall be introduced at the ceiling, and such as ceiling utility pipes, and ledges, such as
returns should be mounted low on the wall, creat- windowsills, should be avoided. The exterior lens
ing a general top-down dilution of area air with surface of ceiling lighting fixtures should be
HEPA-filtered make-up air. Ceiling-mounted re- smooth, mounted flush, and sealed. Any other pen-
turns are not recommended. All HEPA filters etrations through the ceiling or walls shall be
should be efficiency tested using the most pene- sealed. The buffer area shall not contain sources of
trating particle size and should be leak tested at the water (sinks) or floor drains. Work surfaces shall
factory and then leak tested again in situ after in- be constructed of smooth, impervious materials,
stallation.
7
such as stainless steel or molded plastic, so that
Activities and tasks carried out within the buffer they are easily cleaned and disinfected. Carts
area shall be limited to only those necessary when should be of stainless steel wire, nonporous
working within a controlled environment. Only the plastic, or sheet metal construction with good qual-
furniture, equipment, supplies, and other material ity, cleanable casters to promote mobility. Storage
required for the compounding activities to be per- shelving, counters, and cabinets shall be smooth,
formed shall be brought into the area, and they impervious, free from cracks and crevices, non-
shall be nonpermeable, nonshedding, cleanable, shedding, cleanable, and disinfectable; their num-
and resistant to disinfectants. Whenever such items ber, design, and manner of installation shall pro-
are brought into the area, they shall first be cleaned mote effective cleaning and disinfection.
and disinfected. Whenever possible, equipment
and other items used in the buffer area shall not be
Placement of Primary Engineering Controls
taken out of the area except for calibration, servic-
PECs (LAFWs, BSCs, CAIs, and CACIs) shall
ing, or other activities associated with the proper
be located within a restricted access ISO Class 7
maintenance of the item.
(see Table 1) buffer area (see Figure 1), with the
The surfaces of ceilings, walls, floors, fixtures,
following CAI/CACI exceptions below:
shelving, counters, and cabinets in the buffer area
Only authorized personnel and materials re-
shall be smooth, impervious, free from cracks and
quired for compounding and cleaning shall be
crevices, and nonshedding, thereby promoting
permitted in the buffer area.
cleanability and minimizing spaces in which mi-
croorganisms and other contaminants may accu- Presterilization procedures for high-risk level
CSPs, such as weighing and mixing, shall be
7
By definition (IEST RP CC 001.4), HEPA filters are a minimum of
99.97% efficient when tested using 0.3-m thermally generated
completed in no worse than an ISO Class 8
particles and a photometer or rated at their most penetrating particle
size using a particle counter. (seeTable 1) environment.
PECs shall be located out of traffic patterns Viable and Nonviable Environmental
and away from room air currents that could Sampling (ES) Testing
disrupt the intended airflow patterns.
The ES program should provide information to
CAIs and CACIs shall be placed in an ISO Class
staff and leadership to demonstrate that the PEC is
7 (see Table 1) buffer area unless they meet all of
maintaining an environment within the compound-
the following conditions:
ing area that consistently ensures acceptably low
The isolator shall provide isolation from the
viable and nonviable particle levels. The com-
room and maintain ISO Class 5 (see Table 1)
pounding area includes the ISO Class 5 (see Table
during dynamic operating conditions, includ-
1) PEC (LAFWs, BSCs, CAIs, and CACIs), buffer
ing transferring ingredients, components, and
areas, ante-areas, and segregated compounding
devices into and out of the isolator and during
areas.
preparation of CSPs.
Environmental sampling shall occur as part a
Particle counts sampled approximately 6 to 12
comprehensive quality management program and
inches upstream of the critical exposure site
shall occur minimally under any of the following
shall maintain ISO Class 5 (see Table 1) lev-
conditions:
els during compounding operations.
as part of the commissioning and certification
Not more than 3520 particles (0.5 m and of new facilities and equipment;
larger) per m
3
shall be counted during ma-
following any servicing of facilities and
terial transfer, with the particle counter probe
equipment;
located as near to the transfer door as possible
as part of the re-certification of facilities and
without obstructing the transfer.
8
equipment (i.e., every 6 months);
It is incumbent on the compounding personnel to
in response to identified problems with end
obtain documentation from the manufacturer that
products or staff technique; or
the CAI/CACI will meet this standard when lo-
in response to issues with CSPs, observed
cated in environments where the background parti-
compounding personnel work practices, or
cle counts exceed ISO Class 8 (see Table 1) for
patient-related infections (where the CSP is
0.5-m and larger particles. When isolators are
being considered as a potential source of the
used for sterile compounding, the recovery time to
infection).
achieve ISO Class 5 (see Table 1) air quality shall
be documented and internal procedures developed
ENVIRONMENTAL NONVIABLE PARTICLE TESTING
to ensure that adequate recovery time is allowed
PROGRAM
after material transfer before and during com-
A program to sample nonviable airborne parti- pounding operations.
cles differs from that for viable particles in that it
If the PEC is a CAI or CACI that does not meet
is intended to directly measure the performance of
the requirements above or is a LAFW or BSC that
the engineering controls used to create the various
cannot be located within an ISO Class 7 (see Table
levels of air cleanliness, for example, ISO Class 5,
1) buffer area, then only low-risk level nonhazard-
7, or 8 (see Table 1).
ous and radiopharmaceutical CSPs pursuant to a
Engineering Control Performance Verifi-
physician order for a specific patient may be pre-
cationPECs (LAFWs, BSCs, CAIs, and CACIs)
pared, and administration of the CSP shall com-
and secondary engineering controls (buffer and
mence within 12 hours of preparation or as recom-
ante-areas) are essential components of the overall
mended in the manufacturers package insert,
contamination control strategy for aseptic com-
whichever is less.
pounding. As such, it is imperative that they per- 8
Sample procedures are detailed in CETA Applications Guide
CAG-002-2006section 2.09. form as designed and that the resulting levels of
contamination be within acceptable limits. Certifi- than 5 Pa (0.02 inch water column). In facilities
cation procedures such as those outlined in Certi- where low- and medium-risk level CSPs are pre-
fication Guide for Sterile Compounding Facilities pared, differential airflow shall maintain a mini-
(CAG-003-2006)
9
shall be performed by a quali- mum velocity of 0.2 meters per second (40 feet per
fied individual no less than every 6 months and minute) between buffer area and ante-area.
whenever the device or room is relocated or al-
tered or major service to the facility is performed.
ENVIRONMENTAL VIABLE AIRBORNE PARTICLE
Total Particle CountsCertification that each TESTING PROGRAM
ISO classified area, for example, ISO Class 5, 7,
The risk of contaminating a CSP prepared under
and 8 (see Table 1), is within established guide-
low-risk level and medium-risk level conditions is
lines shall be performed no less than every 6
highly dependent on proper hand hygiene and
months and whenever the LAFW, BSC, CAI, or
garbing practices, compounding personnel aseptic
CACI is relocated or the physical structure of the
technique, and the presence of surface contamina-
buffer area or ante-area has been altered. Testing
tion, assuming that all work is performed in a cer-
shall be performed by qualified operators using
tified and properly functioning ISO Class 5 (see
current, state-of-the-art electronic equipment with
Table 1) PEC and secondary engineering controls,
results of the following:
ISO Class 7 (see Table 1) buffer area, and ISO
ISO Class 5: not more than 3520 particles 0.5
Class 8 (see Table 1) ante-area. High-risk level
m and larger size per cubic meter of air for
CSPs pose the greatest threat to patients because
any LAFW, BSC, CAI, and CACI;
compounding personnel are tasked with the re-
ISO Class 7: not more than 352,000 particles
quirement of processing nonsterile components
of 0.5 m size and larger per cubic meter of
and devices in order to achieve sterility.
air for any buffer area;
A sampling program in conjunction with an ob-
ISO Class 8: not more than 3,520,000 parti-
servational audit is designed to evaluate the com-
cles or 0.5 m size and larger per cubic meter
petency of compounding personnel work practices,
of air for any ante-area.
allowing for the implementation of corrective ac-
All certification records shall be maintained and
tions on an ongoing basis (see Personnel Training
reviewed by supervising personnel or other desig-
and Competency Evaluation of Garbing, Aseptic
nated employees to ensure that the controlled envi-
Work Practices and Cleaning/Disinfection
ronments comply with the proper air cleanliness,
Procedures).
room pressures, and ACPHs.
Sampling PlanAn appropriate environmental
sampling plan shall be developed for airborne via-
PRESSURE DIFFERENTIAL MONITORING
ble particles based on a risk assessment of com-
pounding activities performed.
A pressure gauge or velocity meter shall be in-
Selected sampling sites shall include locations
stalled to monitor the pressure differential or air-
within each ISO Class 5 (see Table 1) environment
flow between the buffer area and the ante-area and
and in the ISO Class 7 and 8 (see Table 1) areas
between the ante-area and the general environment
and in the segregated compounding areas at great-
outside the compounding area. The results shall be
est risk of contamination (e.g., work areas near the
reviewed and documented on a log at least every
ISO Class 5 [see Table 1] environment, counters
work shift (minimum frequency shall be at least
near doors, pass-through boxes). The plan shall in-
daily) or by a continuous recording device. The
clude sample location, method of collection, fre-
pressure between the ISO Class 7 (see Table 1)
quency of sampling, volume of air sampled, and
and the general pharmacy area shall not be less
time of day as related to activity in the compound- 9
Controlled Environment Testing Association, 1500 Sunday Drive,
Ste. 102, Raleigh, NC 27607; www.CETAinternational.org. ing area and action levels.
Review of the data generated during a sampling should be given to the overall effect the chosen
event may detect elevated amounts of airborne mi- sampling method will have on the unidirectional
crobial bioburden; such changes may be indicative airflow within a compounding environment.
of adverse changes within the environment. It is
For low-risk level CSPs with 12-hour or less
recommended that compounding personnel refer to
BUD prepared in a PEC (LAFWs, BSCs, CAIs)
Microbiological Evaluation of Clean Rooms and
that maintains an ISO Class 5 (see Table 1), air
Other Controlled Environments 1116 and the
sampling shall be performed at locations inside the
CDCs Guidelines for Environmental Infection
ISO Class 5 (see Table 1) environment and other
Control in Healthcare Facilities, 2003 for more
areas that are in close proximity to the ISO Class 5
information.
(seeTable 1) environment during the certification
Growth MediumA general microbiological
of the PEC.
growth medium such as SoybeanCasein Digest
Air Sampling DevicesThere are a number of
Medium shall be used to support the growth of
manufacturers of electronic air sampling equip-
bacteria. Malt extract agar or some other media
ment. It is important that personnel refer to the
that support the growth of fungi shall be used in
manufacturers recommended procedures when us-
high-risk level compounding environments. Media
ing the equipment to perform volumetric air sam-
used for surface sampling must be supplemented
pling procedures. The instructions in the manufac-
with additives to neutralize the effects of disinfect-
turers users manual for verification and use of
ing agents (e.g., TSA with lecithin and polysorbate
electric air samplers that actively collect volumes
80).
of air for evaluation must be followed. A sufficient
Viable Air SamplingEvaluation of airborne
volume of air (400 to 1000 liters) shall be tested at
microorganisms using volumetric collection meth-
each location in order to maximize sensitivity. The
ods in the controlled air environments (LAFWs,
volumetric air sampling devices need to be serv-
CAIs, clean room or buffer areas, and ante-areas)
iced and calibrated as recommended by the
shall be performed by properly trained individuals
manufacturer.
for all compounding risk levels.
It is recommended that compounding personnel
Impaction shall be the preferred method of volu-
also refer to Methodology and Instrumentation for
metric air sampling. Use of settling plates for qual-
Quantitation of Viable Airborne Microorganisms
itative air sampling may not be able to determine
under Microbiological Evaluation of Clean Rooms
adequately the quality of air in the controlled envi-
and Other Controlled Environments 1116, which
ronment. The settling of particles by gravity onto
provides more information on the use of volu-
culture plates depends on the particle size and may
metric air samplers and volume of air that should
be influenced by air movement. Consequently, the
be sampled to detect environmental bioburden
number of colony-forming units (cfu) on a settling
excursions.
plate may not always relate to the concentrations
of viable particles in the sampled environment. Air Sampling Frequency and ProcessAir
For low-, medium-, and high-risk level com- sampling shall be performed at least semiannually
pounding, air sampling shall be performed at loca- (i.e., every 6 months) as part of the re-certification
tions that are prone to contamination during com- of facilities and equipment. If compounding occurs
pounding activities and during other activities such in multiple locations within an institution (e.g.,
as staging, labeling, gowning, and cleaning. Loca- main pharmacy, satellites), environmental sam-
tions shall include zones of air backwash turbu- pling is required for each individual compounding
lence within LAFW and other areas where air area. A sufficient volume of air shall be sampled
backwash turbulence may enter the compounding and the manufacturers guidelines for use of the
area (doorways, in and around ISO Class 5 [see electronic air sampling equipment followed. Any
Table 1] PEC and environments). Consideration facility construction or equipment servicing may
require that air sampling be performed during rective actions will be dictated by the identifica-
these events. tion of microorganisms recovered (at least the
Incubation PeriodAt the end of the desig- genus level) by an appropriate credentialed labora-
nated sampling or exposure period for air sampling tory of any microbial bioburden captured as a cfu
activities, the microbial growth media plates are using an impaction air sampler. Highly pathogenic
recovered and their covers secured (e.g., taped), microorganisms (e.g., Gram-negative rods, coagu-
and they are inverted and incubated at a tempera- lase positive staphylococcus, molds and yeasts)
ture and for a time period conducive to multiplica- can be potentially fatal to patients receiving CSPs
tion of microorganisms. TSA should be incubated and must be immediately remedied, regardless of
at 30 to 35 for 48 to 72 hours. Malt extract agar cfu count, with the assistance of a competent mi-
or other suitable fungal media should be incubated crobiologist, infection control professional, or in-
at 26 to 30 for 5 to 7 days. The number of dis- dustrial hygienist.
crete colonies of microorganisms are counted and
Table 2. Recommended Action Levels for
reported as cfu and documented on an environ-
Microbial Contamination
*
mental sampling form. Counts from air sampling
(cfu per cubic meter [1000 liters] of air per

need to be transformed into cfu per cubic meter of
plate)
air and evaluated for adverse trends.
Classification Air Sample Action Levels, Documentation, and Data
EvaluationThe value of viable microbial sam-
ISO Class 5 >1
pling of the air in the compounding environment is
ISO Class 7 >10
realized when the data are used to identify and cor-
ISO Class 8 or worse >100
rect an unacceptable situation. Sampling data shall
*
Guidance for IndustrySterile Drug Products Produced by Asep-
tic ProcessingCurrent Good Manufacturing PracticeUS HHS,
be collected and reviewed on a periodic basis as a
FDA September 2004.
means of evaluating the overall control of the com-
pounding environment. If an activity consistently
shows elevated levels of microbial growth, compe-
Additional Personnel Requirements
tent microbiology personnel shall be consulted.
Any cfu count that exceeds its respective action Food, drinks, and materials exposed in patient
level (see Table 2) should prompt a re-evaluation care and treatment areas shall not enter ante-areas,
of the adequacy of personnel work practices, buffer areas, or segregated compounding areas
cleaning procedures, operational procedures, and where components and ingredients of CSPs are
air filtration efficiency within the aseptic com- present. When compounding activities require the
pounding location. An investigation into the manipulation of a patients blood-derived or other
source of the contamination shall be conducted. biological material (e.g., radiolabeling a patients
Sources could include HVAC systems, damaged or donors white blood cells), the manipulations
HEPA filters, and changes in personnel garbing or shall be clearly separated from routine material-
work practices. The source of the problem shall be handling procedures and equipment used in CSP
eliminated, the affected area cleaned, and preparation activities, and they shall be controlled
resampling performed. by specific SOPs in order to avoid any cross-con-
Counts of cfu are to be used as an approximate tamination. Packaged compounding supplies and
measure of the environmental microbial bi- components, such as needles, syringes, tubing sets,
oburden. Action levels are determined on the basis and small- and large-volume parenterals, should be
of cfu data gathered at each sampling location and uncartoned and wiped down with a disinfectant
trended over time. The numbers in Table 2 should that does not leave a residue (e.g., sterile 70%
be used only as guidelines. Regardless of the num- IPA), when possible in an ante-area of ISO Class 8
ber of cfu identified in the pharmacy, further cor- (seeTable 1) air quality, before being passed into
the buffer areas. Personnel hand hygiene and garb- be effective in the presence of light to moderate
ing procedures are also performed in the ante-area, soiling without a pre-cleaning step.
which may contain a sink that enables hands-free Surfaces in LAFWs, BSCs, CAIs, and CACIs,
use with a closed system of soap dispensing to which are intimate to the exposure of critical sites,
minimize the risk of extrinsic contamination. require disinfecting more frequently than do
There shall be some demarcation designation that housekeeping surfaces such as walls and ceilings.
separates the ante-area from the buffer area. Ade- Disinfecting sterile compounding areas shall occur
quate provision for performing antiseptic hand on a regular basis at the intervals noted in Table 3
cleansing usng an alcohol-based surgical hand when spills occur, when the surfaces are visibly
scrub with persistent activity followed by the don- soiled, and when microbial contamination is
ning of sterile gloves should be provided after en- known to have been or is suspected of having been
try into the buffer area. introduced into the compounding areas.
When the surface to be disinfected has heavy
soiling, a cleaning step is recommended prior to
Cleaning and Disinfecting the Compounding
the application of the disinfectant. Trained com-
Area
pounding personnel are responsible for develop-
Environmental contact is a major source of mi-
ing, implementing, and practicing the procedures
crobial contamination of CSPs. Consequently,
for cleaning and disinfecting the DCAs written in
scrupulous attention to cleaning and disinfecting
the SOPs. Cleaning and disinfecting shall occur
the sterile compounding areas is required to mini-
before compounding is performed. Items shall be
mize this as a source of CSP contamination.
removed from all areas to be cleaned, and surfaces
The cleaning and disinfecting practices and fre-
shall be cleaned by removing loose material and
quencies in this section apply to ISO Class 5 (see
residue from spills; for example, water-soluble
Table 1) compounding areas for exposure of criti-
solid residues are removed with sterile water (for
cal sites as well as buffer areas, ante-areas, and
injection or irrigation) and low-shedding wipes.
segregated compounding areas. Compounding per-
This shall be followed by wiping with a residue-
sonnel are responsible for ensuring that the fre-
free disinfecting agent such as sterile 70% IPA,
quency of cleaning is in accordance with the re-
which is allowed to dry before compounding
quirements stated in Table 3 and determining the
begins.
cleaning and disinfecting products to be used (see
Cleaning and disinfecting surfaces in the
Appendix II). Any organizational or institutional
LAFWs, BSCs, CAIs, and CACIs are the most
policies regarding disinfectant selection should be
critical practices before the preparation of CSPs.
considered by compounding personnel. All clean-
Consequently, such surfaces shall be cleaned and
ing and disinfecting practices and policies for the
disinfected frequently, including at the beginning
compounding of CSPs shall be included in written
of each work shift, before each batch preparation
SOPs and shall be followed by all compounding
is started, every 30 minutes during continuous
personnel.
compounding periods of individual CSPs, when
The selection and use of disinfectants in health- there are spills, and when surface contamination is
care facilities is guided by several properties, such known or suspected from procedural breaches.
as microbicidal activity, inactivation by organic Work surfaces in the ISO Class 7 (see Table 1)
matter, residue, and shelf life (see Appendix II). In buffer areas and ISO Class 8 (see Table 1) ante-
general, highly toxic disinfectants, such as glutar- areas as well as segregated compounding areas
aldehyde, are not used on housekeeping surfaces shall be cleaned and disinfected at least daily, and
(e.g., floors, countertops). Many disinfectants reg- dust and debris shall be removed when necessary
istered by the EPA are one-step disinfectants. This from storage sites for compounding ingredients
means that the disinfectant has been formulated to and supplies using a method that does not degrade
the ISO Class 7 or 8 (see Table 1) air quality (see posed of synthetic micro fibers, and dedicated to
Disinfectants and Antiseptics 1072). use in the buffer or clean area, ante-area, and seg-
regated compounding areas and shall not be re-
Table 3. Minimum Frequency of Cleaning and
moved from these areas except for disposal. Floor
Disinfecting Compounding Areas
mops may be used in both the buffer or clean area
Site Minimum Frequency and ante-area, but only in that order. Ideally, all
cleaning tools are discarded after one use by col-
ISO Class 5 (see At the beginning of each
lection in suitable plastic bags and removed with
Table 1) Primary shift, before each batch,
minimal agitation. If cleaning materials (e.g.,
Engineering not longer than 30 min-
mops) are reused, procedures shall be developed
Control (e.g., utes following the previ-
(based on manufacturers recommendations) that
LAFW, BSC, ous surface disinfection
ensure that the effectiveness of the cleaning device
CAI, CACI) when ongoing compound-
is maintained and that repeated use does not add to
ing activities are occur-
the bioburden of the area being cleaned.
ring, after spills, and
when surface contamina-
Supplies and equipment removed from shipping
tion is known or
cartons shall be wiped with a suitable disinfecting
suspected
agent (e.g., sterile 70% IPA) delivered from a
Counters and easi- Daily
spray bottle or other suitable delivery method. Af-
ly cleanable
ter the disinfectant is sprayed or wiped on a sur-
work surfaces
face to be disinfected, the disinfectant shall be al-
Floors Daily lowed to dry, during which time the item shall not
be used for compounding purposes. Walls Monthly
Ceilings Monthly
Wiping with small sterile 70% IPA swabs that
Storage shelving Monthly are commercially available in individual foil-
sealed packages (or a comparable method) is pre-
Floors in the buffer or clean area, ante-area, and
ferred for disinfecting entry points on bags and vi-
segregated compounding area are cleaned by mop-
als, allowing the IPA to dry before piercing stop-
ping with a cleaning and disinfecting agent once
pers with sterile needles and breaking necks of
daily at a time when no aseptic operations are in
ampuls. The surface of the sterile 70% IPA swabs
progress. Mopping shall be performed by trained
used for disinfecting entry points of sterile pack-
personnel using approved agents and procedures
ages and devices shall not contact any other object
described in the written SOPs. It is incumbent on
before contacting the surface of the entry point.
compounding personnel to ensure that such clean-
Sterile 70% IPA wetted gauze pads or other parti-
ing is performed properly. In the buffer or clean
cle-generating material shall not be used to disin-
area, ante-area, and segregated compounding area,
fect the sterile entry points of packages and
walls, ceilings, and shelving shall be cleaned and
devices.
disinfected monthly. Cleaning and disinfecting
When sterile supplies are received in sealed
agents are to be used with careful consideration of
pouches designed to keep them sterile until open-
compatibilities, effectiveness, and inappropriate or
ing, the sterile supplies may be removed from the
toxic residues (see Appendix II). Their schedules
covering pouches as the supplies are introduced
of use and methods of application shall be in ac-
into the ISO Class 5 (see Table 1) PEC (LAFW,
cordance with written SOPs and followed by cus-
BSC, CAI, CACI) without the need to disinfect the
todial or compounding personnel.
individual sterile supply items. No shipping or
All cleaning materials, such as wipers, sponges, other external cartons may be taken into the buffer
and mops, shall be nonshedding, preferably com- or clean area or segregated compounding area.
Personnel Cleansing and Garbing ning of dedicated shoes or shoe covers, head and
facial hair covers (e.g., beard covers in addition to
The careful cleansing of hands and arms and the
face masks), and face masks/eye shields. Eye
correct donning of PPE by compounding personnel
shields are optional unless working with irritants
constitute the first major step in preventing micro-
such as germicidal disinfecting agents or when
bial contamination in CSPs. Personnel shall also
preparing hazardous drugs.
be thoroughly competent and highly motivated to
After donning dedicated shoes or shoe covers,
perform flawless aseptic manipulations with in-
head and facial hair covers, and face masks, a hand
gredients, devices, and components of CSPs.
cleansing procedure shall be performed by remov-
Squamous cells are normally shed from the human
ing debris from underneath fingernails using a nail
body at a rate of 10
6
or more per hour, and those
cleaner under running warm water followed by
skin particles are laden with microorganisms.
10,11
vigorous hand washing. Hands and forearms shall
When individuals are experiencing rashes, sun-
be washed to the elbows for at least 30 seconds
burn, weeping sores, conjunctivitis, active respira-
with soap (either nonantimicrobial or antimicro-
tory infection, as well as when they wear cosmet-
bial) and water while in the ante-area. The use of
ics, they shed these particles at even higher rates.
antimicrobial scrub brushes is not recommended
Particles shed from compounding personnel pose
because they can cause skin irritation and skin
an increased risk of microbial contamination of
damage. Hands and forearms to the elbows will be
critical sites of CSPs. Therefore, compounding
completely dried using either lint-free disposable
personnel with such conditions as mentioned
towels or an electronic hand dryer. After comple-
above shall be excluded from working in ISO
tion of hand washing, a nonshedding gown with
Class 5 (see Table 1) and ISO Class 7 (see Table
sleeves that fit snugly around the wrists and en-
1) compounding areas until their conditions are
closed at the neck is donned. Gowns designated
remedied.
for buffer area use shall be worn, and preferably
Before entering the buffer area or segregated
they should be disposable. If reusable gowns are
compounding area (see Low-Risk Level CSPs with
worn, they should be laundered appropriately for
12-Hour or Less BUD), compounding personnel
buffer area use.
shall remove personal outer garments (e.g., ban-
Once inside the buffer area or segregated com-
dannas, coats, hats, jackets, scarves, sweaters,
pounding area (see Low-Risk Level CSPs with 12-
vests); all cosmetics, because they shed flakes and
Hour or Less BUD), and prior to donning sterile
particles; and all hand, wrist, and other visible jew-
powder-free gloves, antiseptic hand cleansing shall
elry or piercings (e.g., earrings, lip or eyebrow
be performed using a waterless alcohol-based sur-
piercings) that can interfere with the effectiveness
gical hand scrub with persistent activity
12
follow-
of PPE (e.g., fit of gloves and cuffs of sleeves).
ing manufacturers recommendations. Hands are
The wearing of artificial nails or extenders is pro-
allowed to dry thoroughly before donning sterile
hibited while working in the sterile compounding
gloves.
environment. Natural nails shall be kept neat and
Sterile gloves shall be the last item donned be-
trimmed.
fore compounding begins. Gloves become contam-
Personnel shall don the following PPE in an or-
inated when they contact nonsterile surfaces dur-
der that proceeds from those activities considered
ing compounding activities. Disinfection of
the dirtiest to those considered the cleanest. Garb-
contaminated gloved hands may be accomplished
ing activities considered the dirtiest include don-
by wiping or rubbing sterile 70% IPA to all con-
10
Agalloco J , Akers J E. Aseptic Processing: A Vision of the Future.
tact surface areas of the gloves and letting the
Pharmaceutical Technology, 2005. Aseptic Processing supplement,
s16.
12
Guideline for Hand Hygiene in Health care Settings, MMWR,
11
Eaton T. Microbial Risk Assessment for Aseptically Prepared October 25, 2002, vol. 51, No. RR-16 available on the Internet at
Products. Am Pharm Rev. 2005; 8 (5, Sep/Oct): 4651. http://www.cdc.gov/handhygiene/.
gloved hands dry thoroughly. Only use gloves that Personnel Training and Competency
Evaluation of Garbing, Aseptic Work have been tested for compatibility with alcohol
Practices, and Cleaning/Disinfection disinfection by the manufacturer. Routine applica-
Procedures tion of sterile 70% IPA shall occur throughout the
compounding process and whenever nonsterile
Personnel who prepare CSPs shall be trained
surfaces (e.g. vials, counter tops, chairs, carts) are
conscientiously and skillfully by expert personnel
touched. Gloves on hands shall also be routinely
and through multimedia instructional sources and
inspected for holes, punctures, or tears and re-
professional publications in the theoretical princi-
placed immediately if such are detected. Antiseptic
ples and practical skills of garbing procedures,
hand cleansing shall be performed as indicated
aseptic work practices, achieving and maintaining
above. Compounding personnel shall be trained
ISO Class 5 (see Table 1) environmental condi-
and evaluated in the avoidance of touching critical
tions, and cleaning and disinfection procedures.
sites.
This training shall be completed and documented
before any compounding personnel begin to pre-
When compounding personnel exit the com-
pare CSPs. Compounding personnel shall com-
pounding area during a work shift, the exterior
plete didactic training, pass written competence as-
gown may be removed and retained in the com-
sessments, undergo skill assessment using
pounding area if not visibly soiled, to be re-donned
observational audit tools, and media-fill testing
during that same work shift only. However, shoe
(seeAppendices IIIV).
covers, hair and facial hair covers, face masks/eye
Media-fill testing of aseptic work skills shall be
shields, and gloves shall be replaced with new
performed initially before beginning to prepare
ones before re-entering the compounding area, and
CSPs and at least annually thereafter for low- and
proper hand hygiene shall be performed.
medium-risk level compounding and semiannually
During high-risk compounding activities that for high-risk level compounding.
precede terminal sterilization, such as weighing
Compounding personnel who fail written tests or
and mixing of nonsterile ingredients, compounding
observational audits or whose media-fill test vials
personnel shall be garbed and gloved the same as
have one or more units showing visible microbial
when performing compounding in an ISO Class 5
contamination shall be re-instructed and re-evalu-
(see Table 1) environment. Properly garbed and
ated by expert compounding personnel to ensure
gloved compounding personnel who are exposed
correction of all aseptic work practice deficiencies.
to air quality that is either known or suspected to Compounding personnel shall pass all evaluations
be worse than ISO Class 7 (see Table 1) shall re- prior to resuming compounding of sterile prepara-
garb PPE along with washing their hands properly, tions. In addition to didactic evaluation and aseptic
performing antiseptic hand cleansing with a water- media fill, compounding personnel must demon-
less alcohol-based surgical hand scrub, and don- strate proficiency of proper hand hygiene, garbing,
ning sterile gloves upon re-entering the ISO Class and consistent cleaning procedures.
7 (see Table 1) buffer area. When CAIs and
In the event that cleaning and disinfecting proce-
CACIs are the source of the ISO Class 5 (see Ta-
dures are also performed by other support person-
ble 1) environment, the garbing and gloving re- nel (e.g., institutional environmental services,
quirements for compounding personnel should be housekeeping), thorough training of proper hand
as described above, unless the isolator manufac- hygiene, garbing, and cleaning and disinfection
turer can provide written documentation based on procedures shall be done by a qualified aseptic
validated environmental testing that any compo- compounding expert. After completion of training,
nent(s) of PPE or personnel cleansing are not support personnel shall routinely undergo perform-
required. ance evaluation of proper hand hygiene, garbing,
and all applicable cleaning and disinfecting proce- tices (e.g., disinfection of component surfaces,
routine disinfection of gloved hands). dures conducted by a qualified aseptic compound-
Sterile contact agar plates shall be used to sam- ing expert.
ple the gloved fingertips of compounding person-
nel after garbing in order to assess garbing compe-
COMPETENCY EVALUATION OF GARBING AND
tency and after completing the media-fill
ASEPTIC WORK PRACTICE
preparation (without applying sterile 70% IPA) in
order to assess the adequacy of aseptic work prac-
The risk of contaminating a CSP prepared under
tices prior to being initially allowed to prepare
low-risk level and medium-risk level conditions is
CSPs for human use and for more experienced per-
highly dependent on proper hand hygiene and
sonnel to maintain their qualifications to prepare
garbing practices, compounding personnel aseptic
CSPs for human use.
technique, and the presence of surface contamina-
Garbing And Gloving Competency
tion, assuming that all work is performed in a cer-
EvaluationCompounding personnel shall be vi-
tified and properly functioning ISO Class 5 (see
sually observed during the process of performing
Table 1) PEC and secondary engineering controls,
hand hygiene and garbing procedures (see Person-
ISO Class 7 (see Table 1) buffer area, and ISO
nel Cleansing and Garbing under Personnel
Class 8 (see Table 1) ante-area. High-risk level
Training and Evaluation in Aseptic Manipulation
CSPs pose the greatest threat to patients because
Skills above). The visual observation shall be doc-
compounding personnel are tasked with the re-
umented on a form such as the Sample Form for
quirement of processing nonsterile components
Assessing Hand Hygiene and Garbing Related
and devices in order to achieve sterility. Com-
Practices of Compounding Personnel (see Appen-
pounding personnel shall be evaluated initially
dix III) and maintained to provide a permanent rec-
prior to beginning compounding CSPs and when-
ord and long-term assessment of personnel
ever an aseptic media fill is performed using a
competency.
form such as the Sample Form for Assessing Hand
Gloved Fingertip SamplingAll compounding
Hygiene and Garbing Related Practices of Com-
personnel shall successfully complete an initial
pounding Personnel (see Appendix III) and the
competency evaluation and gloved fingertip/thumb
personnel glove fingertip sampling procedures in-
sampling procedure (zero cfu) no less than three
dicated below.
times before initially being allowed to compound
Aseptic Work Practice Assessment and CSPs for human use. Immediately after the com-
Evaluation via Personnel Glove Fingertip pounding employee completes the hand hygiene
SamplingSampling of compounding personnel and garbing procedure (e.g., donning of sterile
glove fingertips shall be performed for all CSP risk gloves prior to any disinfection with sterile 70%
level compounding because direct touch contami- IPA), the evaluator will collect a gloved fingertip
nation is the most likely source of introducing mi- and thumb sample from both hands of the com-
croorganisms into CSPs prepared by humans. pounding employee onto appropriate agar plates
Glove fingertip sampling shall be used to evaluate by lightly pressing each fingertip into the agar.
the competency of personnel in performing hand The plates will be incubated for the appropriate in-
hygiene and garbing procedures in addition to edu- cubation period and at the appropriate temperature
cating compounding personnel on proper work (seeIncubation Period). After completing the ini-
practices, which include frequent and repeated tial gowning and gloving competency evaluation,
glove disinfection using sterile 70% IPA during re-evaluation of all compounding personnel for
actual compounding of CSPs. All personnel shall this competency shall occur at least annually for
demonstrate competency in proper hand hygiene personnel who compound low- and medium-risk
and garbing procedures and in aseptic work prac- level CSPs and semi-annually for personnel who
compound high-risk level CSPs using one or more Media-Fill Test ProcedureThe skill of person-
sample collections during any media-fill test nel to aseptically prepare CSPs shall be evaluated
procedure before they are allowed to continue using sterile fluid bacterial culture media-fill veri-
compounding CSPs for human use. fication, (i.e., sterile bacterial culture medium
transfer via a sterile syringe and needle). Media-
Immediately prior to sampling, gloves shall not
fill testing is used to assess the quality of the asep-
be disinfected with sterile 70% IPA. Disinfecting
tic skill of compounding personnel. Media-fill
gloves immediately before sampling will provide
tests shall represent the most challenging or stress-
false negative results. Plates filled with nutrient
ful conditions actually encountered by the person-
agar with neutralizing agents such as lecithin and
nel being evaluated when they prepare low- and
polysorbate 80 added shall be used when sampling
medium-risk level CSPs and when sterilizing high-
personnel fingertips. Personnel shall touch the
risk level CSPs. Media-fill challenge tests are also
agar with the fingertips of both hands in separate
used to verify the capability of the compounding
plates in a manner to create a slight impression in
environment and processes to produce sterile
the agar. The sampled gloves shall be immediately
preparations.
discarded and proper hand hygiene performed after
A commercially available sterile fluid culture
sampling. The nutrient agar plates shall be incu-
media, such as SoybeanCasein Digest Medium
bated as stated below (see Incubation Period). Re-
(see Sterility Tests 71), that is able to promote
sults should be reported separately as number of
exponential colonization of bacteria that are most
cfu per employee per hand (left hand, right hand).
likely to be transmitted to CSPs from the com-
The cfu action level for gloved hands will be based
pounding personnel and environment is commonly
on the total number of cfu on both gloves, not per
used. For high-risk level CSPs nonsterile commer-
hand.
cially available SoybeanCasein Digest Medium
Incubation PeriodAt the end of the desig-
may be used to make a 3% solution. Normal
nated sampling period for compounding personnel
processing steps, including filter sterilization, shall
competency assessment activities (surface or per-
be mimicked. Media-filled vials shall be incubated
sonnel), the agar plates are recovered and covers
at 20 to 25 or at 30 to 35 for a minimum of 14
secured and they are inverted and incubated at a
days. If two temperatures are used for incubation
temperature and for a time period conducive to
of media-filled samples, then these filled con-
multiplication of microorganisms. TSA with leci-
tainers should be incubated for at least 7 days at
thin and polysorbate 80 shall be incubated at 30
each temperature (see Microbiological Evaluation
to 35 for 48 to 72 hours.
of Clean Rooms and Other Controlled Environ-
Aseptic Manipulation Competency
ments 1116). Failure is indicated by visible tur-
EvaluationAfter successful completion of an
bidity in any one of the media-fill units on or be-
initial Hand Hygiene and Garbing Competency
fore 14 days. Other methodologies recommended
Evaluation, all compounding personnel shall have
by a competent microbiologist to enhance recovery
their aseptic technique and related practice compe-
time and sensitivity to detect microbial contamina-
tency evaluated initially during the Media-Fill Test
tion may be considered (see CSP Microbial Con-
Procedure and subsequent annual or semi-annual
tamination Risk Levels for examples of media-fill
Media-Fill Test Procedures. Records of these
procedures).
evaluations will be maintained using a form such
as the Sample Form for Assessing Aseptic Tech-
SURFACE CLEANING AND DISINFECTION SAMPLING
nique and Related Practices of Compounding Per-
AND ASSESSMENT
sonnel (see Appendix IV) and maintained to pro-
vide a permanent record of and long-term Surface sampling is an important component of
assessment of personnel competency. the maintenance of a suitable microbially con-
trolled environment for compounding CSPs, espe- with a nonshedding wipe soaked in sterile 70%
cially since transfer of microbial contamination IPA.
from improperly disinfected work surfaces via in- If an area is sampled via the swab method, col-
advertent touch contact by compounding personnel lection of the sample is processed by using appro-
can be a potential source of contamination into priate procedures that will result in the surface lo-
CSPs. It is useful for evaluating facility and work cation equivalent to that of a contact plate. After
surface cleaning and disinfecting procedures and swabbing the surface to be sampled, swabs are
employee competency in work practices such as placed in an appropriate diluent; an aliquot is
disinfection of component/vial surface cleaning. planted on or in the specified nutrient agar. Results
Surface sampling shall be performed in all ISO should be reported as cfu per unit of surface area.
classified areas on a periodic basis. Sampling can
be accomplished using contact plates or swabs,
Action Levels, Documentation, and Data
and it shall be done at the conclusion of com-
Evaluation
pounding. Locations to be sampled shall be de-
The value of viable microbial monitoring of
fined in a sample plan or on a form. The size of the
gloved fingertips and surfaces of components and
plate to be used for each sampled location usually
the compounding environment are realized when
ranges from 24 to 30 cm
2
. Contact plates are filled
the data are used to identify and correct an unac-
with general solid agar growth medium and neu-
ceptable work practice. Sampling data shall be col-
tralizing agents above the rim of the plate, and
lected and reviewed on a routine basis as a means
they are used for sampling regular or flat surfaces.
of evaluating the overall control of the compound-
Swabs may be used for sampling irregular sur-
ing environment. If an activity consistently shows
faces, especially for equipment (see Microbiologi-
elevated levels of microbial growth, competent mi-
crobiology personnel shall be consulted.
trolled Environments 1116).
Any cfu count that exceeds its respective action
Cleaning and Disinfecting Competency
level (see Table 4) should prompt a re-evaluation
EvaluationCompounding personnel and other
of the adequacy of personnel work practices,
personnel responsible for cleaning shall be visually
cleaning procedures, operational procedures, and
observed during the process of performing clean-
air filtration efficiency within the aseptic com-
ing and disinfecting procedures, during initial per-
pounding location. An investigation into the
sonnel training on cleaning procedures, during
source of the contamination shall be conducted.
changes in cleaning staff, and at the completion of
Sources could include HVAC systems, damaged
any media-fill test procedure (see Cleaning and
HEPA filters, and changes in personnel garbing or
Disinfecting of Compounding Areas).
working practices. The source of the problem shall
The visual observation shall be documented us-
be eliminated, the affected area cleaned, and
ing a form such as the Sample Form for Assessing
resampling performed.
Cleaning and Disinfection Procedures (see Appen-
When gloved fingertip sample results exceed ac- dix V) and maintained to provide a permanent rec-
tion levels after proper incubation, a review of ord and long-term assessment of personnel
hand hygiene and garbing procedures as well as competency.
glove and surface disinfection procedures and Surface Collection MethodsTo sample sur-
work practices shall be performed and docu- faces using a contact plate, gently touch the sam-
mented. Employee training may be required to cor- ple area with the agar surface and roll the plate
rect the source of the problem. across the surface to be sampled. The contact plate
will leave a growth media residue behind; there- Counts of cfu are to be used as an approximate
fore, immediately after sampling with the contact measure of the environmental microbial bi-
plate, the sampled area shall be thoroughly wiped oburden. Action levels are determined on the basis
of cfu data gathered at each sampling location and and properly disinfected cart or other convey-
trended over time. The numbers in Table 4 should ance for introduction into the buffer area.
be used only as guidelines. Regardless of the num- Manufacturers directions or published data
ber of cfu identified in the compounding facility, for minimum contact time will be followed.
further corrective actions will be dictated by the Individual pouched sterile supplies need not
identification of microorganisms recovered (at be wiped because the pouches can be re-
least the genus level) by an appropriate creden- moved as these sterile supplies are introduced
tialed laboratory of any microbial bioburden cap- into the buffer area.
tured as a cfu using an impaction air sampler. 3. Supplies that are required frequently or other-
Highly pathogenic microorganisms (e.g., Gram- wise needed close at hand but not necessarily
negative rods, coagulase positive staphylococcus, needed for the scheduled operations of the
molds and yeasts) can be potentially fatal to pa- shift are decontaminated and stored on shelv-
tients receiving CSPs and shall be immediately ing in the ante-area.
remedied, regardless of cfu count, with the assis- 4. Carts used to bring supplies from the store-
tance of a competent microbiologist, infection con- room cannot be rolled beyond the demarca-
trol professional, or industrial hygienist. tion line in the ante-area, and carts used in the
buffer area cannot be rolled outward beyond
Table 4. Recommended Action Levels for
the demarcation line unless cleaned and disin-
Microbial Contamination
*
fected before returning.
Classification Fingertip Surface Sample 5. Generally, supplies required for the scheduled
Sample (Contact Plate) operations of the shift are wiped down with
(cfu per plate) an appropriate disinfecting agent and brought
into the buffer area, preferably on one or more
ISO Class 5 >3 >3
movable carts. Supplies that are required for
ISO Class 7 N/A >5
back-up or general support of operations may
ISO Class 8 or N/A >100
be stored on the designated shelving in the
worse
buffer area, but excessive amounts of supplies
*
Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide
to Good Manufacturing Practice for Medicinal Products Annex-
are to be avoided.
es PE 009-6, 5 April 2007.
6. Nonessential objects that shed particles shall
not be brought into the buffer area, including
pencils, cardboard cartons, paper towels, and SUGGESTED STANDARD OPERATING
cotton items (e.g., gauze pads). PROCEDURES (SOPs)
7. Essential paper-related products (e.g., paper
The compounding facility shall have written,
syringe overwraps, work records contained in
properly approved SOPs designed to ensure the
a protective sleeve) shall be wiped down with
quality of the environment in which a CSP is pre-
an appropriate disinfecting agent prior to be-
pared. The following procedures are
ing brought into the buffer area.
recommended:
8. Traffic flow in and out of the buffer area shall
1. Access to the buffer area is restricted to quali-
be minimized.
fied personnel with specific responsibilities or
9. Personnel preparing to enter the buffer area
assigned tasks in the compounding area.
shall remove all personal outer garments, cos-
2. All cartoned supplies are decontaminated in metics (because they shed flakes and parti-
the area by removing them from shipping car- cles), and all hand, wrist, and other visible
tons and wiping or spraying them with a jewelry or piercings that can interfere with the
nonresidue-generating disinfecting agent effectiveness of PPE.
while they are being transferred to a clean 10. Personnel entering the ante-area shall don at-
tire as described in Personnel Cleansing and as to reduce clutter and provide maximum ef-
Garbing and Personnel Training and Compe- ficiency and order for the flow of work.
tency Evaluation of Garbing, Aseptic Work 19. After proper introduction into the DCA of
Practices and Cleaning/Disinfection Pro- supply items required for and limited to the
cedures. assigned operations, they are so arranged that
11. Personnel shall then thoroughly wash hands a clear, uninterrupted path of HEPA-filtered
and forearms to the elbow with soap and wa- air will bathe all critical sites at all times dur-
ter for at least 30 seconds. An air dryer or dis- ing the planned procedures. That is, no ob-
posable nonshedding towels are used to dry jects may be placed between the first air from
hands and forearms after washing. HEPA filters and an exposed critical site.
12. Personnel entering the buffer area shall per-
20. All procedures are performed in a manner de-
form antiseptic hand cleansing prior to don-
signed to minimize the risk of touch contami-
ning sterile gloves using a waterless alcohol-
nation. Gloves are disinfected with adequate
based surgical hand scrub with persistent
frequency with an approved disinfectant such
activity.
as sterile 70% IPA.
13. Chewing gum, drinks, candy, or food items
21. All rubber stoppers of vials and bottles and
shall not be brought into the buffer area or
the necks of ampuls are disinfected by wiping
ante-area. Materials exposed in patient care
with sterile 70% IPA and waiting for at least
and treatment areas shall never be introduced
10 seconds before they are used to prepare
into areas where components and ingredients
CSPs.
for CSPs are present.
22. After the preparation of every CSP, the con-
14. At the beginning of each compounding activ-
tents of the container are thoroughly mixed
ity session, and whenever liquids are spilled,
and then inspected for the presence of particu-
the surfaces of the direct compounding envi-
late matter, evidence of incompatibility, or
ronment are first cleaned with USP Purified
other defects.
Water to remove water-soluble residues. Im-
23. After procedures are completed, used syr-
mediately thereafter, the same surfaces are
inges, bottles, vials, and other supplies are re-
disinfected with a nonresidue-generating
moved, but with a minimum of exit and re-
agent using a nonlinting wipe.
entry into the DCA so as to minimize the risk
15. Primary engineering controls shall be oper-
of introducing contamination into the aseptic
ated continuously during compounding activ-
workspace.
ity. When the blower is turned off and before
other personnel enter to perform compound-
ELEMENTS OF QUALITY CONTROL
ing activities, only one person shall enter the
buffer area for the purposes of turning on the A written description of specific training and
blower (for at least 30 minutes) and disinfect- performance evaluation program for individuals
ing the work surfaces. involved in the use of aseptic techniques for the
16. Traffic in the area of the DCA is minimized preparation of sterile products shall be developed
and controlled. for each site. This program equips personnel with
17. Supplies used in the DCA for the planned the appropriate knowledge and trains them in the
procedures are accumulated and then decon- required skills necessary to perform the assigned
taminated by wiping or spraying the outer sur- tasks. Each person assigned to the aseptic area in
face with sterile 70% IPA or removing the the preparation of sterile products shall success-
outer wrap at the edge of the DCA as the item fully complete specialized training in aseptic tech-
is introduced into the aseptic work area. niques and aseptic area practices prior to preparing
18. All supply items are arranged in the DCA so CSPs (see Personnel Training and Evaluation in
Aseptic Manipulation Skills and Personnel Train- be clearly and indelibly marked on each package
ing and Competency Evaluation of Garbing, Asep- of ingredient. After receipt by the compounding
tic Work Practices and Cleaning/Disinfection facility, packages of ingredients that lack a suppli-
Procedures). ers expiration date cannot be used after 1 year un-
less either appropriate inspection or testing indi-
cates that the ingredient has retained its purity and Ingredients and Devices
quality for use in CSPs.
Compounding personnel ascertain that ingredi-
Careful consideration and evaluation of nonster-
ents for CSPs are of the correct identity and appro-
ile ingredient sources is especially warranted when
priate quality using the following information:
the CSP will be administered into the vascular sys-
vendor labels, labeling, certificates of analysis, di-
tem, central nervous system, or eyes.
rect chemical analysis, and knowledge of com-
Upon receipt of each lot of the bulk drug sub-
pounding facility storage conditions.
stance or excipient used for CSPs, the individual
compounding the preparation performs a visual in-
STERILE INGREDIENTS AND DEVICES
spection of the lot for evidence of deterioration,
Commercially available sterile drug products,
other types of unacceptable quality, and wrong
sterile ready-to-use containers, and devices are ex-
identification. For bulk drug substances or excipi-
amples of sterile components. A written procedure
ents, visual inspection is performed on a routine
for unit-by-unit physical inspection preparatory to
basis as described in the written protocol.
use is followed to ensure that these components
are sterile, free from defects, and otherwise suit-
Equipment
able for their intended use.
It is necessary that equipment, apparatus, and de-
NONSTERILE INGREDIENTS AND DEVICES
vices used to compound a CSP be consistently ca-
pable of operating properly and within acceptable
If any nonsterile components, including con-
tolerance limits. Written procedures outlining re-
tainers and ingredients, are used to make a CSP,
quired equipment calibration, annual maintenance,
such CSPs must be high risk. Nonsterile active in-
monitoring for proper function, and controlled pro-
gredients and added substances or excipients for
cedures for use of the equipment and specified
CSPs should preferably be official USP or NF arti-
time frames for these activities are established and
cles. When nonofficial ingredients are used, they
followed. Routine maintenance and frequencies
shall be accompanied by certificates of analysis
shall be outlined in these SOPs. Results from the
from their suppliers to aid compounding personnel
equipment calibration, annual maintenance reports,
in judging the identity, quality, and purity in rela-
and routine maintenance are kept on file for the
tion to the intended use in a particular CSP. Physi-
lifetime of the equipment. Personnel are prepared
cal inspection of a package of ingredients is neces-
through an appropriate combination of specific
sary in order to detect breaks in the container,
training and experience to operate or manipulate
looseness in the cap or closure, and deviation from
any piece of equipment, apparatus, or device they
the expected appearance, aroma, and texture of the
may use when preparing CSPs. Training includes
contents.
gaining the ability to determine whether any item
Bulk or unformulated drug substances and added
of equipment is operating properly or is
substances or excipients shall be stored in tightly
malfunctioning.
closed containers under temperature, humidity,
and lighting conditions that are either indicated in
official monographs or approved by suppliers. The VERIFICATION OF AUTOMATED
date of receipt by the compounding facility shall COMPOUNDING DEVICES (ACDs) FOR
PARENTERAL NUTRITION racy is then weighed on the balance used in con-
COMPOUNDING junction with the ACD. For example, if 40 mL of
water was used in the volumetric assessment, its
ACDs for the preparation of parenteral nutrition
corresponding weight should be about 40g (as-
admixtures are widely used by pharmacists in hos-
suming the relative density of water is 1.0). In ad-
pitals and other healthcare settings. They are de-
dition, during the use of the ACD, certain addi-
signed to streamline the labor-intensive processes
tives, such as potassium chloride (corrected for
involved in the compounding of these multiple-
density differences), can also be tested in the same
component formulations by automatically deliver-
manner as with an in-process test.
ing the individual nutritional components in a pre-
Finally, additional tests of accuracy may be em-
determined sequence under computerized control.
ployed that determine the content of certain in-
Parenteral nutrition admixtures often contain 20 or
gredients in the final volume of the parenteral nu-
more individual additives representing as many as
trition admixture. Generally, pharmacy
50 or more individual components (e.g., 15 to 20
departments do not have the capability to routinely
crystalline amino acids, dextrose monohydrate,
perform chemical analyses such as analyses of
and lipids; 10 to 12 electrolyte salts; 5 to 7 trace
dextrose or electrolyte concentrations. Conse-
minerals; and 12 vitamins). Thus, ACDs can pro-
quently, hospital or institutional laboratories may
vide improved accuracy and precision of the com-
be called upon to perform these quality assurance
pounding process over the traditional manual com-
tests. However, the methods in such laboratories
pounding methods.
are often designed for biological, not pharmaceuti-
cal, systems. Thus, their testing procedures shall
be verified to meet the USP requirements stated in
Accuracy
the individual monograph for the component being
The accuracy of an ACD can be determined in
tested. For example, under Dextrose Injection, the
various ways to ensure that the correct quantities
following is stated: It contains not less than 95.0%
of nutrients, electrolytes, or other nutritional com-
and not more than 105.0% of the labeled amount
ponents are delivered to the final infusion con-
of C
6
H
12
O
6
H
2
O. The hospital or institutional
tainer. Initially, the ACD is tested for its volume
chemistry laboratories must validate their methods
and weight accuracy. For volume accuracy, a suit-
to apply to this range and correct for their typical
able volume of Sterile Water for Injection, USP,
measurement of anhydrous dextrose versus dex-
which represents a typical additive volume (e.g.,
trose monohydrate. Similar ranges and issues exist,
40 mL for small-volume range of 1 to 100 mL,
for example, for injections of calcium gluconate,
300 mL for large-volume range of 100 to 1000
magnesium sulfate, and potassium chloride. The
mL), is programmed into the ACD and delivered
critical point is the use of USP references and pos-
to the appropriate volumetric container. The com-
sible laboratory procedural differences.
pounding personnel should then consult Volu-
metric Apparatus 31 for appropriate parameters
Precision
to assess the volumetric performance of the ACD.
For gravimetric accuracy, the balance used in con- The intermediate precision of the ACD can be
junction with the ACD is tested using various determined on the basis of the day-to-day varia-
weight sizes that represent the amounts typically tions in performance of the accuracy measures.
used to deliver the various additives. Compound- Thus, compounding personnel shall keep a daily
ing personnel should consult Weights and Bal- record of the above-described accuracy assess-
ances 41 for acceptable tolerances of the weights ments and review the results over time. This re-
used. In addition, the same volume of Sterile Wa- view shall occur at least at weekly intervals to
ter for Injection used to assess volumetric accu- avoid potentially clinically significant cumulative
errors over time. This is especially true for addi- CSP with defects, such as precipitation, cloudi-
tives with a narrow therapeutic index, such as ness, and leakage, which may develop between the
potassium chloride. time of release and the time of distribution, is not
released.
FINISHED PREPARATION RELEASE
Compounding Accuracy Checks
CHECKS AND TESTS
Written procedures for double-checking com-
The following quality metrics shall be performed
pounding accuracy shall be followed for every
for all CSPs before they are dispensed or
CSP during preparation and immediately prior to
administered.
release. The double-check system should meet
state regulations and include label accuracy and
Inspection of Solution Dosage Forms and
accuracy of the addition of all drug products or in-
Review of Compounding Procedures
gredients used to prepare the finished product and
All CSPs that are intended to be solutions shall
their volumes or quantities. The used additive con-
be visually examined for the presence of particu-
tainers and, for those additives for which the entire
late matter and not administered or dispensed
container was not expended, the syringes used to
when such matter is observed. The prescription or-
measure the additive should be quarantined with
ders, written compounding procedure, preparation
the final products until the final product check is
records, and expended materials used to make
completed. Compounding personnel shall visually
CSPs at all contamination risk levels are inspected
confirm that ingredients measured in syringes
for accuracy of correct identities and amounts of
match the written order being compounded. Pref-
ingredients, aseptic mixing and sterilization, pack-
erably, a person other than the compounder can
aging, labeling, and expected physical appearance
verify that correct volumes of correct ingredients
before they are administered or dispensed.
were measured to make each CSP. For example,
compounding personnel would pull the syringe
PHYSICAL INSPECTION
plunger back to the volume measured.
When practical, the accuracy of measurements is
Finished CSPs are individually inspected in ac-
confirmed by weighing a volume of the measured
cordance with written procedures after compound-
fluid, then calculating that volume by dividing the
ing. If not distributed promptly, these CSPs are
weight by the accurate value of the density, or spe-
individually inspected just prior to leaving the
cific gravity, of the measured fluid. Correct den-
storage area. Those CSPs that are not immediately
sity or specific gravity values programmed in
distributed are stored in an appropriate location as
ACDs, which measure by weight using the quo-
described in the written procedures. Immediately
tient of the programmed volume divided by the
after compounding, and as a condition of release,
density or specific gravity, shall be confirmed to
each CSP unit, where possible, should be in-
be accurate before and after delivering volumes of
spected against lighted white or black background
the liquids assigned to each channel or port. These
or both for evidence of visible particulates or other
volume accuracy checks and the following addi-
foreign matter. Prerelease inspection also includes
tional safety and accuracy checks in this section
containerclosure integrity and any other apparent
shall be included in the SOP manual of the CSP
visual defect. CSPs with observed defects should
facility.
be immediately discarded or marked and segre-
gated from acceptable products in a manner that
Sterility Testing
prevents their administration. When CSPs are not
distributed promptly after preparation, a predis- All high-risk level CSPs that are prepared in
tribution inspection is conducted to ensure that a groups of more than 25 identical individual single-
dose packages (e.g., ampuls, bags, syringes, vials) graph or other CSP formula source, the CSP shall
or in multiple-dose vials (MDVs) for administra- not exceed the amount of USP Endotoxin Units
tion to multiple patients or that are exposed longer (per hour per kilogram of body weight or square
than 12 hours at 2 to 8 and longer than 6 hours at meters of body surface area) specified in Bacterial
warmer than 8 before they are sterilized shall Endotoxins Test 85 referenced above for the ap-
meet the sterility test (see Sterility Tests 71) be- propriate route of administration.
fore they are dispensed or administered. The
Identity and Strength Verification of
Membrane Filtration method is the method of
Ingredients
choice where feasible (e.g., components are com-
patible with the membrane). A method not de-
Compounding facilities shall have at least the
scribed in the USP may be used if verification re-
following written procedures for verifying the cor-
sults demonstrate that the alternative is at least as
rect identity and quality of CSPs before they are
effective and reliable as the USP Membrane Fil-
dispensed and administered:
tration method or the USP Direct Inoculation of
1. That labels of CSPs bear correct names and
the Culture Medium method where the Membrane
amounts or concentrations of ingredients, the
Filtration method is not feasible.
total volume, the BUD, the appropriate
When high-risk level CSPs are dispensed before
route(s) of administration, the storage condi-
receiving the results of their sterility tests, there
tions, and other information for safe use.
shall be a written procedure requiring daily obser-
2. That there are correct identities, purities, and
vation of the incubating test specimens and im-
amounts of ingredients by comparing the
mediate recall of the dispensed CSPs when there is
original written order with the written com-
any evidence of microbial growth in the test speci-
pounding record for the CSP.
mens. In addition, the patient and the physician of
3. That correct fill volumes in CSPs and correct
the patient to whom a potentially contaminated
quantities of filled units of the CSPs were ob-
CSP was administered are notified of the potential
tained. When the strength of finished CSPs
risk. Positive sterility test results should prompt a
cannot be confirmed to be accurate, based on
rapid and systematic investigation of aseptic tech-
the above three inspections, the CSPs shall be
nique, environmental control, and other sterility
assayed by methods that are specific for the
assurance controls to identify sources of contami-
active ingredients.
nation and correct problems in the methods or
processes.
STORAGE AND BEYOND-USE DATING
BUDs for compounded preparations are usually
Bacterial Endotoxin (Pyrogen) Testing
assigned on the basis of professional experience,
All high-risk level CSPs, except those for inhala- which should include careful interpretation of ap-
tion and ophthalmic administration, that are pre- propriate information sources for the same or simi-
pared in groups of more than 25 identical individ- lar formulations (see Stability Criteria and Be-
ual single-dose packages (e.g., ampuls, bags, yond-Use Dating under Pharmaceutical
syringes, vials) or in MDVs for administration to CompoundingNonsterile Preparations 795).
multiple patients or that are exposed longer than BUDs for CSPs are rarely based on preparation-
12 hours at 2 to 8 and longer than 6 hours at specific chemical assay results, which are used
warmer than 8 before they are sterilized shall be with the Arrhenius equation to determine expira-
tested to ensure that they do not contain excessive tion dates (see General Notices and Requirements)
bacterial endotoxins (see Bacterial Endotoxins for manufactured products. The majority of CSPs
Test 85 and Pyrogen Test 151). In the absence are aqueous solutions in which hydrolysis of dis-
of a bacterial endotoxins limit in the official mono- solved ingredients is the most common chemical
degradation reaction. The extent of hydrolysis and propriate literature sources or direct testing. BUDs
other heat-catalyzed degradation reactions at any for CSPs that lack justification from either appro-
particular time point in the life of a CSP represents priate literature sources or by direct testing evi-
the thermodynamic sum of exposure temperatures dence shall be assigned as described in Stability
and durations. Such lifetime stability exposure is Criteria and Beyond-Use Dating under Pharma-
represented in the mean kinetic temperature calcu- ceutical CompoundingNonsterile Preparations
lation (see Pharmaceutical Calculations in Pre- 795.
scription Compounding 1160). Drug hydrolysis In addition, compounding personnel may refer to
rates increase exponentially with arithmetic tem- applicable publications to obtain relevant stability,
perature increase; thus, exposure of a beta-lactam compatibility, and degradation information regard-
antibiotic solution for 1 day at controlled room ing the drug or its congeners. When assigning a
temperature (see General Notices and Require- beyond-use date, compounding personnel should
ments) will have an equivalent effect on the extent consult and apply drug-specific and general stabil-
of hydrolysis of approximately 3 to 5 days in cold ity documentation and literature where available,
temperatures (see General Notices and and they should consider the nature of the drug
Requirements). and its degradation mechanism, the container in
which it is packaged, the expected storage condi-
Personnel who prepare, dispense, and administer
tions, and the intended duration of therapy (see Ex-
CSPs shall store them strictly in accordance with
piration Date and Beyond-Use Date under Label-
the conditions stated on the label of ingredient
ing in the General Notices and Requirements).
products and finished CSPs. When CSPs are
Stability information must be carefully interpreted
known to have been exposed to temperatures
in relation to the actual compounded formulation
warmer than the warmest labeled limit or to tem-
and conditions for storage and use. Predictions
peratures exceeding 40 (see General Notices and
based on other evidence, such as publications,
Requirements) for more than 4 hours, such CSPs
charts, and tables, would result in theoretical
should be discarded unless direct assay data or ap-
BUDs. Theoretically predicted beyond-use dating
propriate documentation confirms their continued
introduces varying degrees of assumptions and,
stability.
hence, a likelihood of error or at least inaccuracy.
The degree of error or inaccuracy would be de-
Determining Beyond-Use Dates
pendent on the extent of differences between the
BUDs and expiration dates are not the same (see CSPs characteristics (e.g., composition, concen-
General Notices and Requirements). Expiration tration of ingredients, fill volume, container type
dates for the chemical and stability of manufac- and material) and the characteristics of the prod-
tured sterile products are determined from results ucts from which stability data or information is to
of rigorous analytical and performance testing, and be extrapolated. The greater the doubt of the accu-
they are specific for a particular formulation in its racy of theoretically predicted beyond-use dating,
container and at stated exposure conditions of illu- the greater the need to determine dating periods
mination and temperature. When CSPs deviate experimentally. Theoretically predicted beyond-
from conditions in the approved labeling of manu- use dating periods should be carefully considered
factured products contained in CSPs, compound- for CSPs prepared from nonsterile bulk active in-
ing personnel may consult the manufacturer of gredients having therapeutic activity, especially
particular products for advice on assigning BUDs where these CSPs are expected to be compounded
based on chemical and physical stability parame- routinely. When CSPs will be distributed to and
ters. BUDs for CSPs that are prepared strictly in administered in residential locations other than
accordance with manufacturers product labeling healthcare facilities, the effect of potentially un-
shall be those specified in that labeling or from ap- controlled and unmonitored temperature condi-
tions shall be considered when assigning BUDs. It carried over to the compounded or admixed prepa-
must be ascertained that CSPs will not be exposed ration. Preparation-specific, experimentally deter-
to warm temperatures (see General Notices and mined stability data evaluation protocols are pref-
Requirements) unless the compounding facility has erable to published stability information.
evidence to justify stability of CSPs during such Compounding personnel should consult general in-
exposure. formation chapter Pharmaceutical Stability
It should be recognized that the truly valid evi- 1150 for the appropriate stability parameters to
dence of stability for predicting beyond-use dating be considered when initiating or evaluating a prep-
can be obtained only through product-specific ex- aration-specific stability study.
perimental studies. Semiquantitative procedures
Compounding personnel who assign BUDs to
such as thin-layer chromatography (TLC) may be
CSPs when lacking direct chemical assay results
acceptable for many CSPs. However, quantitative
must critically interpret and evaluate the most ap-
stability-indicating assays such as high-perform-
propriate available information sources to deter-
ance liquid chromatographic (HPLC) assays would
mine a conservative and safe BUD. The SOP man-
be more appropriate for certain CSPs. Examples
ual of the compounding facility and each specific
include CSPs with a narrow therapeutic index,
CSP formula record shall describe the general ba-
where close monitoring or dose titration is re-
sis used to assign the BUD and storage conditions.
quired to ensure therapeutic effectiveness and to
avoid toxicity; where a theoretically established
When manufactured MDVs (see Multiple-Dose
beyond-use dating period is supported by only
Container under Preservation, Packaging, Stor-
marginal evidence; or where a significant margin
age, and Labeling in the General Notices and Re-
of safety cannot be verified for the proposed be-
quirements) of sterile ingredients are used in CSPs,
yond-use dating period. In short, because beyond-
the stoppers of the MDVs are inspected for physi-
use dating periods established from product-spe-
cal integrity and disinfected by wiping with a ster-
cific data acquired from the appropriate instrumen-
ile 70% IPA swab before each penetration with a
tal analyses are clearly more reliable than those
sterile withdrawal device. When contaminants or
predicted theoretically, the former approach is
abnormal properties are suspected or observed in
strongly urged to support dating periods exceeding
MDVs, such MDVs shall be discarded. The BUD
30 days.
after initially entering or opening (e.g., needle
To ensure consistent practices in determining
puncturing) multiple-dose containers is 28 days
and assigning BUDs, the compounding facility
(see Antimicrobial Effectiveness Testing 51) un-
should have written policies and procedures gov-
less otherwise specified by the manufacturer.
erning the determination of the BUDs for all com-
pounded products. When attempting to predict a
theoretical BUD, a compounded or an admixed
Proprietary Bag and Vial Systems
preparation should be considered as a unique sys-
The sterility storage and stability beyond-use tem that has physical and chemical properties and
times for attached and activated (where activated stability characteristics that differ from its compo-
is defined as allowing contact of the previously nents. For example, antioxidant, buffering, or anti-
separate diluent and drug contents) container pairs microbial properties of a sterile vial for injection
of drug products for intravascular administration (SVI) might be lost upon its dilution, with the po-
(e.g., ADD-Vantage
, Mini Bag Plus
) shall be tential of seriously compromising the chemical sta-

applied as indicated by the manufacturer. In other bility of the SVIs active ingredient or the physical
words, follow manufacturers instructions for han- or microbiological stability of the SVI formulation
dling and storing ADD-Vantage
, Mini Bag Plus
, in general. Thus, the properties stabilized in the

Add A Vial
, Add-Ease
products, and any others. SVI formulation usually cannot be expected to be

Monitoring Controlled Storage Areas MAINTAINING STERILITY, PURITY, AND
To ensure that product potency is retained STABILITY OF DISPENSED AND
through the manufacturers labeled expiration date, DISTRIBUTED CSPs
compounding personnel shall monitor the drug
This section summarizes the responsibilities of
storage areas within the compounding facility.
compounding facilities for maintaining quality and
Controlled temperature areas in compounding
control of CSPs that are dispensed and adminis-
facilities include controlled room temperature, 20
tered within their parent healthcare organizations.
to 25 with mean kinetic temperature 25;
Compounding personnel shall ensure proper controlled cold temperature, 2 to 8 with mean
storage and security of CSPs prepared by or dis- kinetic temperature 8; cold temperature, 2 to 8;
pensed from the compounding facility until either freezing temperature, 25 and 10 (see General
their BUDs are reached or they are administered to Notices and Requirements) if needed to achieve
patients. In fulfilling this general responsibility, freezing, and the media-specific temperature range
the compounding facility is responsible for the for microbial culture media. A controlled
proper packaging, handling, transport, and storage temperature area shall be monitored at least once
of CSPs prepared by or dispensed from it, includ- daily and the results documented on a temperature
ing the appropriate education, training, and super- log. Additionally, compounding personnel shall
vision of compounding personnel assigned to these note the storage temperature when placing the
functions. The compounding facility should assist product into or removing the product from the
in the education and training of noncompounding storage unit in order to monitor any temperature
personnel responsible for carrying out any aspect aberrations. Suitable temperature recording
of these functions. devices may include a calibrated continuous
recording device or a National Institute of
Establishing, maintaining, and ensuring compli-
Standards and Technology (NIST) calibrated
ance with comprehensive written policies and pro-
thermometer that has adequate accuracy and
cedures encompassing these responsibilities is a
sensitivity for the intended purpose, and it shall be
further responsibility of the compounding facility.
properly calibrated at suitable intervals. If the
Where noncompounding personnel are assigned
compounding facility uses a continuous
tasks involving any of these responsibilities, the
temperature recording device, compounding
policies and procedures encompassing those tasks
personnel shall verify at least once daily that the
should be developed by compounding supervisors.
recording device itself is functioning properly.
The quality and control activities related to distri-
The temperature-sensing mechanisms shall be
bution of CSPs are summarized in the following
suitably placed in the controlled temperature
five subsections. Activities or concerns that should
storage space to reflect accurately its true
be addressed as the compounding facility fulfills
temperature. In addition, the compounding facility
these responsibilities are as follows.
shall adhere to appropriate procedures of all
controlled storage spaces to ensure that such
Packaging, Handling, and Transport
spaces are not subject to significantly prolonged
temperature fluctuations as may occur, for Inappropriate processes or techniques involved
example, by leaving a refrigerator door open too with packaging, handling, and transport can ad-
long. versely affect quality and package integrity of
CSPs. Although compounding personnel routinely
perform many of the tasks associated with these
functions, some tasks, such as transport, handling,
and placement into storage, may be fulfilled by
noncompounding personnel who are not under the
direct administrative control of the compounding potential breakage and contamination. Special re-
facility. Under these circumstances, appropriate quirements associated with the packaging, trans-
SOPs shall be established by the compounding fa- port, and handling of these agents include the pre-
cility with the involvement of other departments or vention of accidental exposures or spills and the
services whose personnel are responsible for carry- training of personnel in the event of an exposure or
ing out those CSP-related functions for which the spill. Examples of special requirements of these
compounding facility has a direct interest. The per- agents also include exposure-reducing strategies
formance of the noncompounding personnel is such as the use of Luer lock syringes and connec-
monitored for compliance to established policies tions, syringe caps, the capping of container ports,
and procedures. sealed plastic bags, impact-resistant containers,
The critical requirements that are unique to CSPs and cautionary labeling.
and that are necessary to ensure CSP quality and
Use and Storage
packaging integrity shall be addressed in SOPs.
For example, techniques should be specified to
The compounding facility is responsible for en-
prevent the depression of syringe plungers or dis-
suring that CSPs in the patient-care setting main-
lodging of syringe tips during handling and trans-
tain their quality until administered. The immedi-
port. Additionally, disconnection of system com-
ate labeling of the CSP container will display
ponents (e.g., where CSPs are dispensed with
prominently and understandably the requirements
administration sets attached to them) shall be pre-
for proper storage and expiration dating. Delivery
vented through the BUD of the CSP. Foam pad-
and patient-care-setting personnel shall be prop-
ding or inserts are particularly useful where CSPs
erly trained to deliver the CSP to the appropriate
are transported by pneumatic tube systems. Re-
storage location. Outdated and unused CSPs shall
gardless of the methods used, the compounding fa-
be returned to the compounding facility for
cility must evaluate their effectiveness and the reli-
disposition.
ability of the intended protection. Evaluation
SOPs must exist to ensure that storage conditions
should be continuousfor example, through a sur-
in the patient-care setting are suitable for the CSP-
veillance system, including a system of problem
specific storage requirements. Procedures include
reporting to the compounding facility.
daily monitoring and documentation of drug stor-
Inappropriate transport and handling can ad-
age refrigerators to ensure temperatures between
versely affect the quality of certain CSPs having
2 and 8 and the monthly inspection of all drug
unique stability concerns. For example, the physi-
storage locations by compounding personnel. In-
cal shaking that might occur during pneumatic
spections shall confirm compliance with appropri-
tube transport or undue exposure to heat or light
ate storage conditions, separation of drugs and
must be addressed on a preparation-specific basis.
food, proper use of MDVs, and the avoidance of
Alternative transport modes or special packaging
using single-dose products as MDVs. CSPs, as
measures might be needed for the proper assurance
well as all other drug products, shall be stored in
of quality of these CSPs. The use of tamper-evi-
the patient-care area in such a way as to secure
dent closures and seals on CSP ports can add an
them from unauthorized personnel, visitors, and
additional measure of security to ensure product
patients.
integrity regardless of the transport method used.
Chemotoxic and other hazardous CSPs require
Readying for Administration
safeguards to maintain the integrity of the CSP and
to minimize the exposure potential of these prod- Procedures essential for generally ensuring qual-
ucts to the environment and to personnel who may ity, especially sterility assurance, when readying a
come in contact with them. Transportation by CSP for its subsequent administration include
pneumatic tube should be discouraged because of proper hand washing, aseptic technique, site care,
and change of administration sets. Additional pro- Education and Training
cedures may also be essential for certain CSPs, de-
The assurance of CSPs quality and packaging
vices, or techniques. Examples where such special
integrity is highly dependent on the proper adher-
procedures are needed include in-line filtration, the
ence of all personnel to the pertinent SOPs. Com-
operation of automated infusion control devices,
pounding personnel shall design, implement, and
and the replenishment of CSPs into the reservoirs
maintain a formal education, training, and compe-
of implantable or portable infusion pumps. When
tency assessment program that encompasses all the
CSPs are likely to be exposed to warmer than 30
functions and tasks addressed in the foregoing sec-
for more than 1 hour during their administration to
tions and all personnel to whom such functions
patients, the maintenance of their sterility and sta-
and tasks are assigned. This program includes the
bility should be confirmed from either relevant and
assessment and documentation of procedural
reliable sources or direct testing.
breaches, administration mishaps, side effects, al-
lergic reactions, and complications associated with
Redispensed CSPs
dosage or administration, such as extravasation.
The compounding facility shall have the sole au- This program should be coordinated with the insti-
thority to determine when unopened, returned tutions adverse-events and incident reporting
CSPs may be redispensed. Returned CSPs may be programs.
redispensed only when personnel responsible for
Packing and Transporting CSPs
sterile compounding can ensure that such CSPs are
sterile, pure, and stable (contain labeled strength of
The following sections describe how to maintain
ingredients). The following may provide such as-
sterility and stability of CSPs until they are deliv-
surance: the CSPs were maintained under continu-
ered to patient care locations for administration.
ous refrigeration and protected from light, if re-
quired, and no evidence of tampering or any
PACKING CSPs FOR TRANSIT
readying for use outside the compounding facility
exists. Assignment of new storage times and When CSPs are distributed to locations outside
BUDs that exceed the original dates for returned the premises in which they are compounded, com-
CSPs is permitted only when there is supporting pounding personnel select packing containers and
evidence from sterility testing and quantitative as- materials that are expected to maintain physical in-
say of ingredients. Thus, initial preparation and tegrity, sterility, and stability of CSPs during
thaw times should be documented and reliable transit. Packing is selected that simultaneously
measures should have been taken to prevent and protects CSPs from damage, leakage, contamina-
detect tampering. Compliance with all procedures tion, and degradation, and protects personnel who
associated with maintaining product quality is es- transport packed CSPs from harm. The SOP man-
sential. The CSPs shall not be redispensed if there ual of the compounding facility specifically de-
is not adequate assurance that preparation quality scribes appropriate packing containers and insulat-
and packaging integrity (including the connections ing and stuffing materials, based on information
of devices, where applicable) were continuously from product specifications, vendors, and experi-
maintained between the time the CSPs left and the ence of compounding personnel. Written instruc-
time they were returned. Additionally, CSPs shall tions that clearly explain how to safely open con-
not be redispensed if redispensing cannot be sup- tainers of packed CSPs are provided to patients
ported by the originally assigned BUD. and other recipients.
TRANSIT OF CSPs tional objectives for the training program include
all home care responsibilities expected of the pa-
Compounding facilities that ship CSPs to loca-
tient or caregiver and is specified in terms of pa-
tions outside their own premises shall select modes
tient or caregiver competencies.
of transport that are expected to deliver properly
Upon the conclusion of the training program, the
packed CSPs in undamaged, sterile, and stable
patient or caregiver should, correctly and consis-
condition to recipients.
tently, be able to do the following:
Compounding personnel should ascertain that
1. Describe the therapy involved, including the
temperatures of CSPs during transit by the selected
disease or condition for which the CSPs are
mode will not exceed the warmest temperature
prescribed, goals of therapy, expected thera-
specified on the storage temperature range on CSP
peutic outcome, and potential side effects of
labels. It is recommended that compounding per-
the CSPs.
sonnel communicate directly with the couriers to
2. Inspect all drug products, CSPs, devices,
learn shipping durations and exposure conditions
equipment, and supplies on receipt to ensure
that CSPs may encounter.
that proper temperatures were maintained dur-
Compounding personnel shall include specific
ing transport and that goods received show no
handling and exposure instructions on the exteriors
evidence of deterioration or defects.
of containers packed with CSPs to be transported
3. Handle, store, and monitor all drug products,
and obtain reasonable assurance of compliance
CSPs, and related supplies and equipment in
therewith from transporters. Compounding person-
the home, including all special requirements
nel shall periodically review the delivery perform-
related to same.
ance of couriers to ascertain that CSPs are being
4. Visually inspect all drug products, CSPs, de-
efficiently and properly transported.
vices, and other items the patient or caregiver
is required to use immediately prior to admin-
Storage in Locations Outside Compounding
istration in a manner to ensure that all items
Facilities
are acceptable for use. For example, CSPs
must be free from leakage, container cracks,
Compounding facilities that ship CSPs to pa-
particulates, precipitate, haziness, discolora-
tients and other recipients outside their own prem-
tion, or other deviations from the normal ex-
ises shall ascertain or provide, whichever is appro-
pected appearance, and the immediate pack-
priate, the following assurances:
ages of sterile devices must be completely
1. Labels and accessory labeling for CSPs in-
sealed, with no evidence of loss of package
clude clearly readable BUDs, storage instruc-
integrity.
tions, and disposal instructions for out-of-date
5. Check labels immediately prior to administra-
units.
tion to ensure the right drug, dose, patient,
2. Each patient or other recipient is able to store
and time of administration.
the CSPs properly, including the use of a
6. Clean the in-home preparation area, scrub
properly functioning refrigerator and freezer
hands, use proper aseptic technique, and man-
if CSPs are labeled for such storage.
ipulate all containers, equipment, apparatus,
devices, and supplies used in conjunction with
PATIENT OR CAREGIVER TRAINING
administration.
A formal training program is provided as a 7. Employ all techniques and precautions associ-
means to ensure understanding and compliance ated with CSP administration; for example,
with the many special and complex responsibilities preparing supplies and equipment, handling
placed on the patient or caregiver for the storage, of devices, priming the tubing, and discontin-
handling, and administration of CSPs. The instruc- uing an infusion.
8. Care for catheters, change dressings, and PATIENT MONITORING AND ADVERSE
maintain site patency as indicated. EVENTS REPORTING
9. Monitor for and detect occurrences of thera-
Compounding facilities shall clinically monitor
peutic complications such as infection, phle-
patients treated with CSPs according to the regu-
bitis, electrolyte imbalance, and catheter
lations and guidelines of their respective state
misplacement.
healthcare practitioner licensure boards or of ac-
10. Respond immediately to emergency or critical
cepted standards of practice. Compounding facili-
situations such as catheter breakage or dis-
ties shall provide patients and other recipients of
placement, tubing disconnection, clot forma-
CSPs with a way to address their questions and re-
tion, flow blockage, and equipment
port any concerns that they may have with CSPs
malfunction.
and their administration devices.
11. Know when to seek and how to obtain profes-
The SOP manuals of compounding facilities
sional emergency services or professional
shall describe specific instructions for receiving,
advice.
acknowledging, and dating receipts, and for re-
12. Handle, contain, and dispose of wastes, such
cording, or filing, and evaluating reports of ad-
as needles, syringes, devices, biohazardous
verse events and of the quality of preparation
spills or residuals, and infectious substances.
claimed to be associated with CSPs. Reports of ad-
Training programs include a hands-on demon- verse events with CSPs shall be reviewed
stration and practice with actual items that the pa- promptly and thoroughly by compounding super-
tient or caregiver is expected to use, such as CSP visors to correct and prevent future occurrences.
containers, devices, and equipment. The patient or Compounding personnel are encouraged to partici-
caregiver practices aseptic and injection technique pate in adverse event reporting and product defects
under the direct observation of a health programs of the FDA and USP.
professional.
The compounding facility, in conjunction with QUALITY ASSURANCE (QA) PROGRAM
nursing or medical personnel, is responsible for
A provider of CSPs shall have in place a formal
ensuring initially and on an ongoing basis that the
QA program intended to provide a mechanism for
patient or caregiver understands, has mastered, and
monitoring, evaluating, correcting, and improving
is capable of and willing to comply with all of
the activities and processes described in this chap-
these home care responsibilities. This is achieved
ter. Emphasis in the QA program is placed on
through a formal, written assessment program. All
maintaining and improving the quality of systems
specified competencies in the patient or caregiver
and the provision of patient care. In addition, the
training program are formally assessed. The pa-
QA program ensures that any plan aimed at cor-
tient or caregiver is expected to demonstrate to ap-
recting identified problems also includes appropri-
propriate healthcare personnel mastery of assigned
ate follow-up to make certain that effective correc-
activities before being allowed to administer CSPs
tive actions were performed.
13
unsupervised by a health professional.
Characteristics of a QA program include the
Printed material such as checklists or instruc-
following:
tions provided during training may serve as contin-
1. Formalization in writing;
uing post-training reinforcement of learning or as
2. Consideration of all aspects of the prepara-
reminders of specific patient or caregiver responsi-
tions and dispensing of products as described
bilities. Post-training verbal counseling can also be
used periodically, as appropriate, to reinforce
13
The use of additional resources, such as the Accreditation Manual
for Home Care from the J oint Commission on Accreditation of
training and to ensure continuing correct and com-
Healthcare Organizations, may prove helpful in the development of
plete fulfillment of responsibilities. a QA plan.
in this chapter, including environmental test- 6. Delineation of the individuals responsible for
ing and verification results; each aspect of the QA program.
3. Description of specific monitoring and evalu- In developing a specific plan, focus is on estab-
ation activities; lishing objective, measurable indicators for moni-
4. Specification of how results are to be reported toring activities and processes that are deemed
and evaluated; high risk, high volume, or problem prone. In gen-
5. Identification of appropriate follow-up mech- eral, the selection of indicators and the effective-
anisms when action limits or thresholds are ness of the overall QA program is reassessed on an
exceeded; and annual basis.
ABBREVIATIONS AND ACRONYMS
ACD automated compounding device
ACPH air changes per hour
ALARA as low as reasonably achievable
ASHRAE American Society of Heating, Refrigerating
and Air-Conditioning Engineers
BI biological indicator
BSC biological safety cabinet
BUD beyond-use date
CACI compounding aseptic containment isolator
CAI compounding aseptic isolator
CDC Centers for Disease Control and Prevention
CETA Controlled Environment Testing Associa-
tion
cfu colony-forming unit(s)
CSP compounded sterile preparation
CSTD closed-system vial-transfer device
DCA direct compounding area
ECV endotoxin challenge vial
EU Endotoxin Unit
FDA Food and Drug Administration
HEPA high efficiency particulate air
HICPAC Healthcare Infection Control Practices Ad-
visory Committee
HVAC heating, ventilation, and air conditioning
IPA isopropyl alcohol
ISO International Organization for Standardiza-
tion
LAFW laminar airflow workbench
MDVs multiple-dose vials
MMWR Morbidity and Mortality Weekly Report
NIOSH National Institute for Occupational Safety
and Health
NIST National Institute of Standards and Tech-
nology
PEC primary engineering control
PET positron emission tomography
PPE personnel protective equipment
psi pounds per square inch
QA quality assurance
SOP standard operating procedure
SVI sterile vial for injection
TSA trypticase soy agar
USP United States Pharmacopeia
APPENDICES
Appendix I. Principal Competencies, Conditions, Practices, and Quality Assurances That Are Required ( shall) and
Recommended ( should) in USP Chapter 797
NOTEThis tabular appendix selectively abstracts and condenses the full text of 797 for rapid reference only. Compounding
personnel are responsible for reading, understanding and complying with the full text and all official USP terminology, content, and
conditions therein.
INTRODUCTION
Chapter purpose is to prevent harm and death to patients treated with CSPs.
Chapter pertains to preparation, storage, and transportation, but not administration, of CSPs.
Personnel and facilities to which 797 applies; therefore, for whom and which it may be enforced by regulatory and accreditation
authorities.
Types of preparations designated to be CSPs according to their physical forms, and their sites and routes of administration to patients.
Compounding personnel must be meticulously conscientious to preclude contact contamination of CSPs both within and outside ISO
Class 5 areas.
ORGANIZATION
All compounding personnel shall be responsible for understanding fundamental practices and precautions within USP 797, for
developing and implementing appropriate procedures, and for continually evaluating these procedures and the quality of final CSPs to
prevent harm.
DEFINITIONS
Twenty-eight terms are defined and integral to complying with USP 797.
RESPONSIBILITY OF COMPOUNDING PERSONNEL
Practices and quality assurances required to prepare, store, and transport CSPs that are sterile, and acceptably accurate, pure, and
stable.
CSP MICROBIAL CONTAMINATION RISK LEVELS
Proper training and evaluation of personnel, proper cleansing and garbing of personnel, proper cleaning and disinfecting of
compounding work environments, and proper maintenance and monitoring of controlled environmental locations (all of which are
detailed in their respective sections).
Low-Risk Level CSPs
Aseptic manipulations within an ISO Class 5 environment using three or fewer sterile products and entries into any container.
In absence of passing sterility test, store not more than 48 hours at controlled room temperature, 14 days at cold temperature, and 45
days in solid frozen state at 25 to 10 or colder.
Media-fill test at least annually by compounding personnel.
Low-Risk Level CSPs with 12-Hour or Less BUD
Fully comply with all four specific criteria.
Sinks should not be located adjacent to the ISO Class 5 primary engineering control.
Sinks should be separated from the immediate area of the ISO Class 5 primary engineering control device.
Medium-Risk Level CSPs
Aseptic manipulations within an ISO Class 5 environment using prolonged and complex mixing and transfer, more than three sterile
products and entries into any container, and pooling ingredients from multiple sterile products to prepare multiple CSPs.
Media-fill test at least annually by compounding personnel.
High-Risk Level CSPs
Confirmed presence of nonsterile ingredients and devices, or confirmed or suspected exposure of sterile ingredients for more than one
hour to air quality inferior to ISO Class 5 before final sterilization.
Sterilization method verified to achieve sterility for the quantity and type of containers.
Meet allowable limits for bacterial endotoxins.
Maintain acceptable strength and purity of ingredients and integrity of containers after sterilization.
Media-fill test at least semiannually by compounding personnel.
PERSONNEL TRAINING AND EVALUATION IN ASEPTIC MANIPULATIONS SKILLS
Pass didactic, practical skill assessment and media-fill testing initially, followed by an annual assessment for a low- and medium-risk
level compounding and semi-annual assessment for high-risk level compounding.
Compounding personnel who fail written tests, or whose media-fill test vials result in gross microbial colonization, shall be
immediately reinstructed and re-evaluated by expert compounding personnel to ensure correction of all aseptic practice deficiencies.
IMMEDIATE-USE CSPs
Fully comply with all six specified criteria.
SINGLE-DOSE AND MULTIPLE-DOSE CONTAINERS
Beyond-use date 28 days, unless specified otherwise by the manufacturer, for closure sealed multiple-dose containers after initial
opening or entry.
Beyond-use time of 6 hours, unless specified otherwise by the manufacturer, for closure sealed single-dose containers in ISO Class 5
or cleaner air after initial opening or entry.
Beyond-use time of 1 hour for closure sealed single-dose containers after being opened or entered in worse than ISO Class 5 air.
Storage of opened single-dose ampuls is not permitted.
HAZARDOUS DRUGS AS CSPs
Appropriate personnel protective equipment.
Appropriate primary engineering controls (BSCs and CACIs) are used for concurrent personnel protection and exposure of critical
sites.
Hazardous drugs shall be stored separately from other inventory in a manner to prevent contamination and personnel exposure.
At least 0.01 inch water column negative pressure and 12 air changes per hour in non-cleanrooms in which CACIs are located.
Hazardous drugs shall be handled with caution at all times using appropriate chemotherapy gloves during receiving, distribution,
stocking, inventorying, preparing for administration, and disposal.
Hazardous drugs shall be prepared in an ISO Class 5 environment with protective engineering controls in place, and following aseptic
practices specified for the appropriate contamination risk levels.
Access to drug preparation areas shall be limited to authorized personnel.
A pressure indicator shall be installed that can readily monitor room pressurization, which is documented daily.
Annual documentation of full training of personnel regarding storage, handling, and disposal of hazardous drugs.
When used, a CSTD shall be used in an ISO Class 5 primary engineering control device.
At least 0.01 inch water column negative pressure is required for compounding of hazardous drugs.
Negative-pressure buffer area is not required for low-volume compounding operations when CSTD is used in BSC or CACI.
Compounding personnel of reproductive capability shall confirm in writing that they understand the risks of handling hazardous drugs.
Disposal of all hazardous drug wastes shall comply with all applicable federal and state regulations.
Total external exhaust of primary engineering controls.
Assay of surface wipe samples every 6 months.
RADIOPHARMACEUTICALS AS CSPs
Positron Emission Tomography is according to USP chapter 823.
Appropriate primary engineering controls and radioactivity containment and shielding.
Radiopharmaceuticals compounded from sterile components, in closed sterile containers, with volume of 100 mL or less for a single-
dose injection or not more than 30 mL taken from a multiple-dose container shall be designated as and conform to the standards for
low-risk level CSPs.
Radiopharmaceutical vials, designed for multi-use, compounded with technetium-99m, exposed to ISO Class 5 environment and
punctured by needles with no direct contact contamination may be used up to the time indicated by manufacturers recommendations.
Location of primary engineering controls permitted in ISO Class 8 controlled environment.
Technetium-99m/Molybdenum-99 generators used according to manufacturer, state, and federal requirements.
Radiopharmaceuticals prepared as low-risk level CSPs with 12-hour or less BUD shall be prepared in a segregated compounding area.
Materials and garb exposed in patient-care and treatment area shall not cross a line of demarcation into the segregated compounding
area.
Technetium-99m/Molybdenum-99 generators must be eluted in ISO Class 8 conditions.
Segregated compounding area will be designated with a line of demarcation
Storage and transport of properly shielded vials of radiopharmaceutical CSPs may occur in a limited access ambient environment
without a specific ISO class designation.
ALLERGEN EXTRACTS AS CSPs
Allergen extracts as CSPs are not subject to the personnel, environmental, and storage requirements for all CSP Microbial
Contamination Risk Levels when certain criteria are met.
VERIFICATION OF COMPOUNDING ACCURACY AND STERILITY
Review labels and document correct measurements, aseptic manipulations, and sterilization procedures to confirm correct identity,
purity, and strength of ingredients in, and sterility of, CSPs.
Assay finished CSPs to confirm correct identity and, or, strength of ingredients.
Sterility test finished CSPs.
Sterilization Methods
Verify that methods achieve sterility while maintaining appropriate strength, purity, quality, and packaging integrity.
Prove effectiveness by USP chapter 71, equivalent, or superior sterility testing.
Sterilization of High-Risk Level CSPs by Filtration
Nominal 0.2-m pore size sterile membranes that are chemically and physically compatible with the CSP.
Complete rapidly without filter replacement.
Subject filter to manufacturers recommended integrity test (e.g., bubble point test) after filtering CSPs.
Sterilization of High-Risk Level CSPs by Steam
Test to verify the mass of containers to be sterilized will be sterile after the selected exposure duration in the particular autoclave.
Ensure live steam contacts all ingredients and surfaces to be sterilized.
Pass solutions through a 1.2-m or smaller nominal pore size filter into final containers to remove particulates before sterilization.
Heated filtered air shall be evenly distributed throughout the chamber by a blower device.
Dry heat shall only be used for those materials that cannot be sterilized by steam, when the moisture would either damage or be
impermeable to the materials.
Sufficient space shall be left between materials to allow for good circulation of the hot air.
The description of dry heat sterilization conditions and duration for specific CSPs shall be included in written documentation in the
compounding facility. The effectiveness of dry heat sterilization shall be verified using appropriate biological indicators and other
confirmation.
The oven should be equipped with a system for controlling temperature and exposure period.
Depyrogenation by Dry Heat
Dry heat depyrogenation shall be used to render glassware or containers, such as vials free from pyrogens as well as viable microbes.
The description of the dry heat depyrogenation cycle and duration for specific load items shall be included in written documentation
in the compounding facility.
The effectiveness of the dry heat depyrogenation cycle shall be verified using endotoxin challenge vials (ECVs).
The bacterial endotoxin test should be performed on the ECVs to verify the cycle is capable of achieving a 3 log reduction in
endotoxin.
ENVIRONMENTAL QUALITY AND CONTROL
Exposure of Critical Sites
ISO Class 5 or better air.
Preclude direct contact (e.g., touch and secretions) contamination.
ISO Class 5 Air Sources, Buffer Areas, and Ante-Areas
A buffer area is an area that provides at least ISO Class 7 air quality.
New representations of facility layouts.
Each compounding facility shall ensure that each source of ISO Class 5 environment for exposure of critical sites and sterilization by
filtration is properly located, operated, maintained, monitored, and verified.
Placement of devices (e.g., computers and printers) and objects (e.g., carts and cabinets) can be placed in buffer areas and shall be
verified by testing or monitoring.
Viable and Nonviable Environmental Sampling (ES) Testing
Environmental sampling shall occur as part a comprehensive quality management program and shall occur minimally when several
conditions exist.
The ES program should provide information to staff and leadership to demonstrate that the engineering controls are maintaining an
environment within the compounding area that consistently maintains acceptably low viable and nonviable particle levels.
Environmental Nonviable Particle Testing Program
Certification and testing of primary (LAFWs, BSCs, CAIs and CACIs) and secondary engineering controls (buffer and ante areas)
shall be performed by a qualified individual no less than every six months and whenever the device or room is relocated, altered, or
major service to the facility is performed. Certification procedures such as those outlined in the CETA Certification Guide for Sterile
Compounding Facilities (CAG-003-2006) shall be used.
Total Particle Counts
Certification that each ISO classified area (e.g., ISO Class 5, 7 and 8) is within established guidelines shall be performed no less than
every 6 months and whenever the LAFW, BSC, CAI, or CACI is relocated or the physical structure of the buffer room or ante-area
has been altered.
Testing shall be performed by qualified operators using current, state-of-the-art electronic equipment with results meeting ISO Class 5,
7, or 8 depending on the requirements of the area.
All certification records shall be maintained and reviewed by supervising personnel or other designated employee to ensure that the
controlled environments comply with the proper air cleanliness, room pressures, and air changes per hour.
Pressure Differential Monitoring
A pressure gauge or velocity meter shall be installed to monitor the pressure differential or airflow between the buffer area and ante-
area and the ante-area and the general environment outside the compounding area.
The results shall be reviewed and documented on a log at least every work shift (minimum frequency shall be at least daily) or by a
continuous recording device.
The pressure between the ISO Class 7 and general pharmacy area shall not be less than 5 Pa (0.02 inch water column (w.c.).
In facilities where low- and medium-risk level CSPs are prepared, differential airflow shall maintain a minimum velocity of 0.2
meter/second (40 fpm) between buffer area and ante-area.
Environmental Viable Airborne Particle Testing ProgramSampling Plan
An appropriate environmental sampling plan shall be developed for airborne viable particles based on a risk assessment of
compounding activities performed.
Selected sampling sites shall include locations within each ISO Class 5 environment and in the ISO Class 7 and 8 areas, and the
segregated compounding areas at greatest risk of contamination (e.g., work areas near the ISO Class 5 environment, counters near
doors, pass-through boxes).
The plan shall include sample location, method of collection, frequency of sampling, volume of air sampled, and time of day as
related to activity in the compounding area and action levels.
It is recommended that compounding personnel refer to USP Chapter Microbiological Evaluation of Clean Rooms and Other
Controlled Environments 1116 and the CDC Guidelines for Environmental Infection Control in Healthcare Facilities-2003 for more
information.
Growth Media
A general microbiological growth medium such as SoybeanCasein Digest Medium (also known as trypticase soy broth (TSB) or agar
(TSA)) shall be used to support the growth of bacteria.
Malt extract agar (MEA) or some other media that supports the growth of fungi shall be used in high-risk level compounding
environments.
Media used for surface sampling shall be supplemented with additives to neutralize the effects of disinfecting agents (e.g., TSA with
lecithin and polysorbate 80).
Viable Air Sampling
Evaluation of airborne microorganisms using volumetric collection methods in the controlled air environments shall be performed by
properly trained individuals for all compounding risk levels.
Impaction shall be the preferred method of volumetric air sampling.
For low-, medium-, and high-risk level compounding, air sampling shall be performed at locations that are prone to contamination
during compounding activities and during other activities like staging, labeling, gowning, and cleaning.
Locations shall include zones of air backwash turbulence within laminar airflow workbench and other areas where air backwash
turbulence may enter the compounding area.
For low-risk level CSPs with 12-hour or less BUD, air sampling shall be performed at locations inside the ISO Class 5 environment
and other areas that are in close proximity to the ISO class 5 environment, during the certification of the primary engineering control.
Consideration should be given to the overall effect the chosen sampling method will have on the unidirectional airflow within a
compounding environment.
Air Sampling Devices
The instructions in the manufacturers user manual for verification and use of electric air samplers that actively collect volumes of air
for evaluation shall be followed.
A sufficient volume of air (4001000 liters) shall be tested at each location in order to maximize sensitivity.
It is recommended that compounding personnel also refer to USP Chapter 1116 that can provide more information on the use of
volumetric air samplers and volume of air that should be sampled to detect environmental bioburden excursions.
Air Sampling Frequency and Process
Air sampling shall be performed at least semiannually (i.e. every 6 months), as part of the re-certification of facilities and equipment
for area where primary engineering controls are located.
A sufficient volume of air shall be sampled and the manufacturers guidelines for use of the electronic air sampling equipment
followed.
Any facility construction or equipment servicing may require the need to perform air sampling during these events.
Incubation Period
The microbial growth media plates used to collect environmental sampling are recovered, covers secured (e.g., taped), inverted, and
incubated at a temperature and for a time period conducive to multiplication of microorganisms.
The number of discrete colonies of microorganisms shall be counted and reported as colony-forming units (cfu) and documented on
an environmental monitoring form. Counts from air monitoring need to be transformed into cfu/cubic meter of air and evaluated for
adverse trends.
TSA should be incubated at 35 2 for 23 days.
MEA or other suitable fungal media should be incubated at 28 2 for 57 days.
Action Levels, Documentation and Data Evaluation
Sampling data shall be collected and reviewed on a periodic basis as a means of evaluating the overall control of the compounding
environment.
Competent microbiology personnel shall be consulted if an environmental sampling consistently shows elevated levels of microbial
growth.
An investigation into the source of the environmental contamination shall be conducted.
Any cfu count that exceeds its respective action level should prompt a re-evaluation of the adequacy of personnel work practices,
cleaning procedures, operational procedures, and air filtration efficiency within the aseptic compounding location.
Table titled, Recommended Action Levels for Microbial Contamination should only be used as a guideline
Facility Design and Environmental Controls
Compounding facilities are physically designed and environmentally controlled to minimize airborne contamination from contacting
critical sites.
Compounding facilities shall provide a comfortable and well-lighted working environment, which typically includes a temperature of
20 or cooler to maintain comfortable conditions for compounding personnel when attired in the required aseptic compounding garb.
Primary engineering controls provide unidirectional (i.e., laminar) HEPA air at a velocity sufficient to prevent airborne particles from
contacting critical sites.
In situ air pattern analysis via smoke studies shall be conducted at the critical area to demonstrate unidirectional airflow and sweeping
action over and away from the product under dynamic conditions.
Policies and procedures for maintaining and working within the primary engineering control area shall be written and followed. The
policies and procedures will be determined by the scope and risk levels of the aseptic compounding activities used during the
preparation of the CSPs.
The principles of HEPA-filtered unidirectional airflow in the work environment shall be understood and practiced in the compounding
process in order to achieve the desired environmental conditions.
Clean rooms for nonhazardous and nonradioactive CSPs are supplied with HEPA that enters from ceilings with return vents low on
walls, and provide not less than 30 air changes per hour.
Buffer areas maintain 0.02- to 0.05-inch water column positive pressure, and do not contain sinks or drains.
Air velocity from buffer rooms or zones to ante-areas is at least 40 feet/minute.
The primary engineering controls shall be placed within a buffer area in such a manner as to avoid conditions that could adversely
affect their operation.
The primary engineering controls shall be placed out of the traffic flow and in a manner to avoid disruption from the HVAC system
and room cross-drafts.
HEPA-filtered supply air shall be introduced at the ceiling.
All HEPA filters shall be efficiency tested using the most penetrating particle size and shall be leak tested at the factory and then leak
tested again in situ after installation.
Activities and tasks carried out within the buffer area shall be limited to only those necessary when working within a controlled
environment.
Only the furniture, equipment, supplies, and other material required for the compounding activities to be performed shall be brought
into the room.
Surfaces and essential furniture in buffer rooms or zones and clean rooms shall be nonporous, smooth, nonshedding, impermeable,
cleanable, and resistant to disinfectants.
The surfaces of ceilings, walls, floors, fixtures, shelving, counters, and cabinets in the buffer area shall be smooth, impervious, free
from cracks and crevices, and nonshedding, thereby promoting cleanability and minimizing spaces in which microorganisms and other
contaminants may accumulate.
The surfaces shall be resistant to damage by disinfectant agents.
J unctures of ceilings to walls shall be coved or caulked to avoid cracks and crevices where dirt can accumulate.
Ceiling tiles shall be caulked around each perimeter to seal them to the support frame.
The exterior lens surface of ceiling lighting fixtures shall be smooth, mounted flush, and sealed.
Any other penetrations through the ceiling or walls shall be sealed.
The buffer area shall not contain sources of water (sinks) or floor drains. Work surfaces shall be constructed of smooth, impervious
materials, such as stainless steel or molded plastic, so that they are easily cleaned and disinfected.
Recommended ( should) in USP Chapter 797 (Continued)
Carts shall be of stainless steel wire, nonporous plastic, or sheet metal construction with good quality, cleanable casters to promote
mobility.
Storage shelving, counters, and cabinets shall be smooth, impervious, free from cracks and crevices, nonshedding, cleanable, and
disinfectable.
Their number, design, and manner of installation the itmes above shall promote effective cleaning and disinfection.
If ceilings consist of inlaid panels, the panels should be impregnated with a polymer to render them impervious and hydrophobic.
Dust-collecting overhangs, such as ceiling utility pipes, or ledges, such as windowsills, should be avoided.
Air returns should be mounted low on the wall creating a general top-down dilution of room air with HEPA-filtered make-up air.
Placement Of Primary Engineering Controls Within Iso Class 7 Buffer Areas
Primary engineering controls for nonhazardous and nonradioactive CSPs are located in buffer areas, except for CAIs that are proven
to maintain ISO Class 5 air when particle counts are sampled 6 to 12 inches upstream of critical site exposure areas during
performance of normal inward and outward transfer of materials, and compounding manipulations when such CAIs are located in air
quality worse than ISO Class 7.
Presterilization procedures for high-risk level CSPs, such as weighing and mixing, shall be completed in no worse than an ISO Class
8 environment.
Primary engineering controls shall be located out of traffic patterns and away from room air currents that could disrupt the intended
airflow patterns.
When isolators are used for sterile compounding, the recovery time to achieve ISO Class 5 air quality shall be documented and
internal procedures developed to ensure that adequate recovery time is allowed after material transfer before and during compounding
operations.
When compounding activities require the manipulation of a patients blood-derived or other biological material (e.g., radiolabeling a
patients or a donors white blood cells), the manipulations shall be clearly separated from routine material-handling procedures and
equipment used in CSP preparation activities, and they shall be controlled by specific standard operating procedures in order to avoid
any cross-contamination.
Food, drinks, and items exposed in patient care areas, and unpacking of bulk supplies and personnel cleansing and garbing are
prohibited from buffer areas or rooms.
Demarcation designation between buffer areas or rooms and ante-areas.
Antiseptic hand cleansing and sterile gloves in buffer areas or rooms.
Packaged compounding supplies and components, such as needles, syringes, tubing sets, and small- and large-volume parenterals,
should be uncartoned and wiped down with a disinfectant that does not leave a residue (e.g., sterile 70% IPA) when possible in an
ante-area, of ISO Class 8 air quality, before being passed into the buffer areas.
Cleaning and Disinfecting the Sterile Compounding Areas
Trained personnel write detailed procedures including cleansers, disinfectants, and non-shedding wipe and mop materials.
Cleaning and disinfecting surfaces in the LAFWs, BSCs, CAIs, and CACIs shall be cleaned and disinfected frequently including at
the beginning of each work shift, before each batch preparation is started, every 30 minutes during continuous compounding periods
of individual CSPs, when there are spills, and when surface contamination is known or suspected from procedural breaches.
Trained compounding personnel are responsible for developing, implementing, and practicing the procedures for cleaning and
disinfecting the DCAs written in the SOPs.
Cleaning and disinfecting shall occur before compounding is performed. Items shall be removed from all areas to be cleaned and
surfaces shall be cleaned by removing loose material and residue from spills, e.g., water-soluble solid residues are removed with
Sterile Water (for Injection or Irrigation) and low-shedding wipes. This shall be followed by wiping with a residue-free disinfecting
agent, such as sterile 70% IPA, which is allowed to dry before compounding begins.
Work surfaces in ISO Class 7 and 8 areas and segregated compounding areas are cleaned at least daily.
Dust and debris shall be removed when necessary from storage sites for compounding ingredients and supplies, using a method that
does not degrade the ISO Class 7 or 8 air quality.
Floors in ISO Class 7 and 8 areas are cleaned daily when no compounding occurs.
IPA (70% isopropyl alcohol) remains on surfaces to be disinfected for at least 30 seconds before such are used to prepare CSPs.
Emptied shelving, walls, and ceilings in ante-areas are cleaned and disinfected at least monthly.
Mopping shall be performed by trained personnel using approved agents and procedures described in the written SOPs.
Cleaning and disinfecting agents, their schedules of use and methods of application shall be in accordance with written SOPs and
followed by custodial and/or compounding personnel.
All cleaning materials, such as wipers, sponges, and mops, shall be nonshedding, preferably composed of synthetic micro fibers, and
dedicated to use in the buffer area, or ante-area, and segregated compounding areas and shall not be removed from these areas except
for disposal.
If cleaning materials are reused (e.g., mops), procedures shall be developed (based on manufacturer recommendations) that ensure that
the effectiveness of the cleaning device is maintained and repeated use does not add to the bioburden of the area being cleaned.
Supplies and equipment removed from shipping cartons shall be wiped with a suitable disinfecting agent (e.g., sterile 70% IPA)
delivered from a spray bottle or other suitable delivery method.
After the disinfectant is sprayed or wiped on a surface to be disinfected, the disinfectant shall be allowed to dry, and during this time
the item shall not be used for compounding purposes.
Sterile 70% IPA wetted gauze pads or other particle-generating material shall not be used to disinfect the sterile entry points of
packages and devices.
Personnel Cleansing And Garbing
Personnel shall also be thoroughly competent and highly motivated to perform flawless aseptic manipulations with ingredients,
devices, and components of CSPs.
Personnel with rashes, sunburn, weeping sores, conjunctivitis, active respiratory infection, and cosmetics are prohibited from preparing
CSPs.
Compounding personnel remove personal outer garments; cosmetics; artificial nails; hand, wrist, and body jewelry that can interfere
with the fit of gowns and gloves; and visible body piercing above the neck.
Order of compounding garb and cleansing in ante-area: shoes or shoe covers, head and facial hair covers, face mask, fingernail
cleansing, hand and forearm washing and drying; non-shedding gown.
Order of cleansing and gloving in buffer room or area: hand cleansing with a persistently active alcohol-based product with persistent
activity, allow hands to dry; don sterile gloves.
Routinely disinfect gloves with sterile 70% IPA after contacting nonsterile objects.
Inspect gloves for holes and replace when breaches are detected.
Personnel repeat proper procedures after they are exposed to direct contact contamination or worse than ISO Class 8 air.
These requirements are exempted only for immediate use CSPs and CAIs for which manufacturers provide written documentation
based on validated testing that such personnel practices are not required to maintain sterility in CSPs.
Personnel Training And Competency Evaluation Of Garbing, Aseptic Work Practices And Cleaning/Disinfection Procedures
Personnel who prepare CSPs shall be trained conscientiously and skillfully by expert personnel, multi-media instructional sources, and
professional publications in the theoretical principles and practical skills of garbing procedures, aseptic work practices, achieving and
maintaining ISO Class 5 environmental conditions, and cleaning and disinfection procedures.
This training shall be completed and documented before any compounding personnel begin to prepare CSPs.
Compounding personnel shall complete didactic training, pass written competence assessments, undergo skill assessment using
observational audit tools, and media-fill testing.
Media-fill testing of aseptic work skills shall be performed initially before beginning to prepare CSPs and at least annually thereafter
for low- and medium-risk level compounding; and semiannually for high-risk level compounding.
Compounding personnel who fail written tests, observational audits, or whose media-fill test vials have one or more units showing
visible microbial contamination, shall be reinstructed and re-evaluated by expert compounding personnel to ensure correction of all
aseptic work practice deficiencies.
Compounding personnel shall pass all evaluations prior to resuming compounding of sterile preparations.
Compounding personnel must demonstrate proficiency of proper hand hygiene, garbing, and consistent cleaning procedures in addition
to didactic evaluation and aseptic media fill.
Cleaning and disinfecting procedures performed by other support personnel shall be thoroughly trained in proper hand hygiene, and
garbing, cleaning, and disinfection procedures by a qualified aseptic compounding expert.
Support personnel shall routinely undergo performance evaluation of proper hand hygiene, garbing, and all applicable cleaning and
disinfecting procedures conducted by a qualified aseptic compounding expert.
Competency Evaluation of Garbing and Aseptic Work Practices
Compounding personnel shall be evaluated initially prior to beginning compounding CSPs and whenever an aseptic media fill is
performed using a Sample Form for Assessing Hand Hygiene and Garbing Related Practices of Compounding Personnel and the
personnel glove fingertip sampling procedures
Aseptic Work Practice Assessment and Evaluation via Personnel Glove Fingertip Sampling
Monitoring of compounding personnel glove finger tips shall be performed for all CSP risk level compounding.
Glove fingertip sampling shall be used to evaluate the competency of personnel in performing hand hygiene and garbing procedures in
addition to educating compounding personnel on proper work practices.
All personnel shall demonstrate competency in proper hand hygiene and garbing procedures in addition to aseptic work practices.
Sterile contact agar plates shall be used to sample the gloved fingertips of compounding personnel after garbing to assess garbing
competency and after completing the media-fill preparation.
Gloves shall not be disinfected with sterile 70% IPA immediately prior to sampling.
Garbing and Gloving Competency Evaluation
Compounding personnel shall be visually observed during the process of performing hand hygiene and garbing procedures.
The visual observation shall be documented on a Sample Form for Assessing Hand Hygiene and Garbing Related Practices of
Compounding Personnel and maintained to provide a permanent record of and long-term assessment of personnel competency.
Gloved Fingertip Sampling
Immediately after the compounder completes the hand hygiene and garbing procedure, the evaluator shall collect a gloved fingertip
and thumb sample from both hands of the compounder onto appropriate agar plates by lightly pressing each finger tip into the agar.
The plates shall be incubated for the appropriate incubation period and at the appropriate temperature.
All employees shall successfully complete an initial competency evaluation and gloved fingertip/thumb sampling procedure (0 cfu) no
less than three times before initially being allowed to compound CSPs for human use.
After completing the initial gowning and gloving competency evaluation, re-evaluation of all compounding personnel shall occur at
least annually for low- and medium-risk level CSPs and semiannually for high-risk level CSPs before being allowed to continue
compounding CSPs.
Gloves shall not be disinfected with sterile 70% IPA prior to testing.
The sampled gloves shall be immediately discarded and proper hand hygiene performed after sampling. The nutrient agar plates shall
be incubated as stated below.
The cfu action level for gloved hands shall be based on the total number of cfu on both gloves and not per hand.
Results should be reported separately as number of cfu per employee per hand (left hand, right hand).
Incubation Period
At the end of the designated sampling period, the agar plates are recovered, covers secured, inverted and incubated at a temperature
and for a time period conducive to multiplication of microorganisms. Trypticase soy agar (TSA) with lecithin and polysorbate 80
shall be incubated at 35 2 for 23 days.
Aseptic Manipulation Competency Evaluation
All compounding personnel shall have their aseptic technique and related practice competency evaluated initially during the media-fill
test procedure and subsequent annual or semiannual media-fill test procedures on the Sample Form for Assessing Aseptic Technique
and Related Practices of Compounding Personnel.
Media-Fill Test Procedure
The skill of personnel to aseptically prepare CSPs shall be evaluated using sterile fluid bacterial culture media-fill verification.
Media-filled vials shall be incubated within a range of 35 2 for 14 days.
Surface Cleaning and Disinfection Sampling and Assessment
Surface sampling shall be performed in all ISO classified areas on a periodic basis and can be accomplished using contact plates
and/or swabs and shall be done at the conclusion of compounding
Locations to be sampled shall be defined in a sample plan or on a form.
Cleaning and Disinfecting Competency Evaluation
Compounding personnel and other personnel responsible for cleaning shall be visually observed during the process of performing
cleaning and disinfecting procedures during initial personnel training on cleaning procedures, changes in cleaning staff and at the
completion of any Media-Fill Test Procedure.
Visual observation shall be documented on a Sample Form for Assessing Cleaning and Disinfection Procedures and maintained to
provide a permanent record of, and long-term assessment of, personnel competency.
Surface Collection Methods
Immediately after sampling a surface with the contact plate, the sampled area shall be thoroughly wiped with a non-shedding wipe
soaked in sterile 70% IPA.
Results should be reported as cfu per unit of surface area.
Action Levels, Documentation, and Data Evaluation
Environmental sampling data shall be collected and reviewed on a routine basis as a means of evaluating the overall control of the
compounding environment.
If an activity consistently shows elevated levels of microbial growth, competent microbiology personnel shall be consulted.
An investigation into the source of the contamination shall be conducted.
When gloved fingertip sample results exceeds action levels after proper incubation, a review of hand hygiene and garbing procedures
as well as glove and surface disinfection procedures and work practices shall be performed and documented.
Any cfu count that exceeds its respective action level should prompt a re-evaluation of the adequacy of personnel work practices,
cleaning procedures, operational procedures, and air filtration efficiency within the aseptic compounding location.
SUGGESTED STANDARD OPERATING PROCEDURES
All facilities are required to have these, and they must include at least the items enumerated in this section.
FINISHED PREPARATION RELEASE CHECKS AND TESTS
Inspection of Solution Dosage Forms and Review of Compounding Procedures
Review procedures and documents to ensure sterility, purity, correct identities and amounts of ingredients, and stability.
Visually inspect for abnormal particulate matter and color, and intact containers and seals.
Sterility Testing
High-risk level CSPs prepared in batches of more than 25 identical containers, or exposed longer than 12 hours at 2 to 8 and 6
hours at warmer than 8 before being sterilized.
Bacterial Endotoxin (Pyrogen) Testing
High-risk level CSPs, excluding those for inhalation and ophthalmic administration, prepared in batches of more than 25 identical
containers, or exposed longer than 12 hours at 2 to 8 and 6 hours at warmer than 8 before being sterilized.
Identity and Strength Verification of Ingredients
Written procedures to verify correct identity, quality, amounts, and purities of ingredients used in CSPs.
Written procedures to ensure labels of CSPs contain correct names and amounts or concentrations of ingredients, total volumes,
beyond-use dates, storage conditions, and route(s) of administration.
STORAGE AND BEYOND-USE DATING
Determining Beyond-Use Dates
Use the general criteria in USP 795 in the absence of direct stability-indicating assays or authoritative literature that supports longer
durations.
MAINTAINING STERILITY, PURITY, AND STABILITY OF DISPENSED AND DISTRIBUTED CSPs
Written procedures for proper packaging, storage, and transportation conditions to maintain sterility, quality, purity, and strength of
CSPs.
Redispensed CSPs
When sterility, and acceptable purity, strength, and quality can be ensured.
Assignment of sterility storage times and stability beyond-use dates that occur later than those of originally dispensed CSPs must be
based on results of sterility testing and quantitative assay of ingredients.
Packaging And Transporting CSPs
Packaging maintains physical integrity, sterility, stability, and purity of CSPs.
Modes of transport that maintain appropriate temperatures and prevent damage to CSPs.
PATIENT OR CAREGIVER TRAINING
Multiple component formal training program to ensure patients and caregivers understand the proper storage, handling, use, and
disposal of CSPs.
PATIENT MONITORING AND ADVERSE EVENTS REPORTING
Written standard procedures describe means for patients to ask questions and report concerns and adverse events with CSPs, and for
compounding supervisors to correct and prevent future problems.
Adverse events and defects with CSPs reported to FDAs MedWatch and USPs MEDMARX programs.
Appendix III. Sample Form for Assessing Hand Hygiene and Garbing Related Practices of Compounding Personnel
Printed name and position/title of person assessed:
Name of facility or location:
Hand Hygiene and Garbing Practices: The qualified evaluator will mark () each space for which the person being assessed has
acceptably completed the described activity, prints N/A if the activity is not applicable to the assessment session or N/O if the
activity was not observed.
*
Presents in a clean appropriate attire and manner.
Wears no cosmetics or jewelry (watches, rings, earrings, etc. piercing jewelry included) upon entry into ante-areas.
Brings no food or drinks into or stored in the ante-areas or buffer areas.
Is aware of the line of demarcation separating clean and dirty sides and observes required activities.
Dons shoe covers or designated clean-area shoes one at a time, placing the covered or designated shoe on clean side of
the line of demarcation, as appropriate.
Dons beard cover if necessary.
Dons head cover assuring that all hair is covered.
Dons face mask to cover bridge of nose down to include chin.
Performs hand hygiene procedure by wetting hands and forearms and washing using soap and warm water for at least 30
seconds.
Dries hands and forearms using lint-free towel or hand dryer.
Selects the appropriate sized gown examining for any holes, tears, or other defects.
Dons gown and ensures full closure.
Disinfects hands again using a waterless alcohol-based surgical hand scrub with persistent activity and allows hands to
dry thoroughly. before donning sterile gloves
Dons appropriate sized sterile gloves ensuring that there is a tight fit with no excess glove material at the fingertips.
Examines gloves ensuring that there are no defects, holes, or tears.
While engaging in sterile compounding activities, routinely disinfects gloves with sterile 70% IPA prior to work in the
direct compounding area (DCA) and after touching items or surfaces that may contaminate gloves.
Removes PPE on the clean side of the ante-area.
Removes gloves and performs hand hygiene.
Removes gown and discards it, or hangs it on hook if it is to be reused within the same work day.
Removes and discards mask, head cover, and beard cover (if used).
Removes shoe covers or shoe one at a time, ensuring that uncovered foot is placed on the dirty side of the line of
demarcation and performs hand hygiene again. (Removes and discards shoe covers every time the compounding area is
exited).
*
The person assessed is immediately informed of all unacceptable activities (i.e., spaces lacking a Check marks, N/A, or N/O)
and shown and informed of specific corrections.
Signature of Person Assessed Printed Name Date
Signature of Qualified Evaluator Printed Name Date
Appendix IV. Sample Form for Assessing Aseptic Technique and Related Practices of Compounding Personnel
Aseptic Technique, Safety, and Quality Assurance Practices: The qualified evaluator will mark () each space for which the person
being assessed has acceptably completed the described activity, prints N/A if the activity is not applicable to the assessment session
or N/O if the activity was not observed.
*
Completes the Hand Hygiene and Garbing Competency Assessment Form.
Performs proper hand hygiene, garbing, and gloving procedures according to SOPs.
Disinfects ISO Class 5 device surfaces with an appropriate agent.
Disinfects components/vials with an appropriate agent prior to placing into ISO Class 5 work area.
Introduces only essential materials in a proper arrangement in the ISO Class 5 work area.
Does not interrupt, impede, or divert flow of first-air to critical sites.
Ensures syringes, needles, and tubing remain in their individual packaging and are only opened in ISO Class 5 work area
Performs manipulations only in the appropriate DCA of the ISO Class 5 device.
Does not expose critical sites to contact contamination or worse than ISO Class 5 air.
Disinfects stoppers, injection ports, and ampul necks by wiping with sterile 70% IPA and allows sufficient time to dry.
Affixes needles to syringes without contact contamination.
Punctures vial stoppers and spikes infusion ports without contact contamination.
Labels preparation(s) correctly.
Disinfects sterile gloves routinely by wiping with sterile 70% IPA during prolonged compounding manipulations.
Cleans, sets up, and calibrates automated compounding device (e.g., TPN compounder) according to manufacturers
instructions.
Disposes of sharps and waste according to institutional policy or recognized guidelines.
*
Appendix V. Sample Form for Assessing Cleaning and Disinfection Procedures
Cleaning and Disinfection Practices: The qualified evaluator will mark () each space for which the person being assessed has
acceptably completed the described activity, prints N/A if the activity is not applicable to the assessment session or N/O if the
activity was not observed.
*
Daily Tasks:
Prepares correct concentration of disinfectant solution according to manufacturers instructions.
Uses appropriately labeled container for the type of surface to be cleaned (floor, wall, production bins, etc.).
Documents disinfectant solution preparation.
Follows garbing procedures when performing any cleaning activities.
At the beginning of each shift, cleans all ISO Class 5 devices prior to compounding in the following order: walls, IV bar,
automated compounders, and work surface.
Uses a lint free wipe soaked with sterile 70% IPA or other approved disinfectant solution and allows to dry completely.
Removes all compounder components and cleans all ISO Class 5 areas as stated above at the end of each shift.
Cleans all counters and easily cleanable work surfaces.
Mops floors, using the mop labeled floors, starting at the wall opposite the room entry door; mops floor surface in even
strokes toward the operator. Moves carts as needed to clean entire floor surface. Use of a microfiber cleaning system
is an acceptable alternative to mops.
In the ante-area, cleans sink and all contact surfaces; cleans floor with a disinfectant solution or uses microfiber cleaning
system.
Monthly Tasks:
Performs monthly cleaning on a designated day. Prepares a disinfectant solution as stated in daily tasks that is
appropriate for the surfaces to be cleaned.
Cleans buffer area and ante-area ceiling, walls, and storage shelving with a disinfectant solution and a mop or uses a
microfiber cleaning system.
Once ISO Class 5 area is clean, cleans compounding room ceiling, followed by walls and ending with the floor. Uses
appropriate labeled mops or microfiber cleaning system.
Cleans all buffer area totes and storage shelves by removing contents and using a germicidal detergent soaked lint free
wipe, cleans the inside surfaces of the tote and then the entire exterior surfaces of the tote. Allows totes to dry. Prior to
replacing contents into tote, wipes tote with sterile 70% IPA to remove disinfectant residue. Uses new wipe as needed.
Cleans all buffer area carts by removing contents and using germicidal detergent soaked lint free wipe, cleans all carts
starting with the top shelf and top of post, working down to wheels. Cleans the under side of shelves in a similar
manner. Uses a new wipe for each cart. Allows to dry. Wipes carts with sterile 70% IPA wetted lint-free wipe to
remove any disinfectant residue. Uses new wipe as needed.
Cleans buffer area chairs, the interior and exterior of trash bins, and storage bins using disinfectant solution soaked lint
free wipe.
Documents all cleaning activities as to who performed such activities with date and time noted.
*
(Official J une 1, 2008)

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Revision Bulletin 797 Pharmaceutical CompoundingSterile Preparations 1

Change to read: quality standards for CSPs of drugs and nutrients

(cfu per cubic meter [1000 liters] of air per

, Mini Bag Plus

) shall be tential of seriously compromising the chemical sta-

, Mini Bag Plus

, in general. Thus, the properties stabilized in the

products, and any others. SVI formulation usually cannot be expected to be

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